Treatment for tumors driven by metabolic dysfunction

ABSTRACT

The present disclosure relates to modified or polymer conjugated MetAP2 inhibitors. The present disclosure also relates to methods of treating metabolically-driven diseases and disorders, such as certain cancers.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and the benefit of, U.S. Ser. No.62/277,293, filed on Jan. 11, 2016, U.S. Ser. No. 62/393,929, filed onSep. 13, 2016 and U.S. Ser. No. 62/395,446, filed on Sep. 16, 2016. Thecontents of each application are incorporated herein by reference in itsentirety.

FIELD OF THE DISCLOSURE

The present disclosure provides compounds, pharmaceutical compositionsand methods for treating patients with a proliferation disorder, such ascancer, complicated by metabolic dysfunction. The disclosure relates tothe fields of biomedicine, pharmacology, and molecular biology.

BACKGROUND OF THE DISCLOSURE

It is well established that obesity and metabolic dysfunction are riskfactors for a person to develop cancer. However, there is no specifictreatment regimen for metabolically dysfunctional people once they arediagnosed with cancer or proliferation related disorders. Recentdiscoveries in cancer research have revealed complex interactionsbetween certain cancer patient's endocrine health and the progression oftheir cancer that center on metabolic factors, adipose tissue-derivedhormones and the chronic inflammation that accompanies excess visceraladiposity. In select cancers, these adipose tissue-derived hormonesstimulate specific oncogenic pathways, thereby increasing cancer cellproliferation, invasiveness and ultimately, killing the patient fasterthan cancer patients with normal physiologic levels of these metabolicfactors. Other visceral adipose tissue-derived hormones play aprotective role in cancer, and are often suppressed with excess visceraladiposity. Despite the fact that this cancer/metabolic nexus is reportedto result directly in over 80,000 deaths annually in the U.S. alone,there are no treatments specifically designed for this disease nexus andpatient population.

Accordingly, new compounds, pharmaceutical compositions and methods fortreating patients with proliferation disorder, such as cancer,complicated by metabolic dysfunction are needed. The present disclosureaddresses these needs.

SUMMARY OF THE DISCLOSURE

The present disclosure provides methods of treating, or ameliorating atleast one symptom of, a proliferation disorder, such as cancer, in asubject in need thereof, comprising administering at least one compoundof the present disclosure in a therapeutically effective amount to thesubject to treat the proliferation disorder, wherein the subject has ametabolic dysfunction.

The present disclosure also provides methods of treating ametabolically-sensitive tumor in a subject in need thereof comprisingadministering at least one compound of the present disclosure in atherapeutically effective amount to the subject to treat themetabolically-sensitive tumor, wherein the subject has a metabolicdysfunction.

In one aspect, the present disclosure provides a method for treating, orameliorating at least one symptom of, cancer or treating ametabolically-sensitive tumor in a subject in need thereof comprisingadministering at therapeutically effective amount of at least onecompound of the Formula

-   -   wherein, independently for each occurrence,    -   R₄ is H or C₁-C₆ alkyl;    -   R₅ is H or C₁-C₆ alkyl;    -   R₆ is C₂-C₆ hydroxyalkyl;    -   Z is —NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-L or        —NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-Q-X—Y—C(O)—W;    -   AA₁ is glycine, alanine, or H₂N(CH₂)_(m)CO₂H, wherein m is 2, 3,        4 or 5;    -   AA₂ is a bond, or alanine, cysteine, aspartic acid, glutamic        acid, phenylalanine, glycine, histidine, isoleucine, lysine,        leucine, methionine, asparagine, proline, glutamine, arginine,        serine, threonine, valine, tryptophan, or tyrosine;    -   AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic        acid, phenylalanine, glycine, histidine, isoleucine, lysine,        leucine, methionine, asparagine, proline, glutamine, arginine,        serine, threonine, valine, tryptophan, or tyrosine;    -   AA₄ is a bond, or alanine, cysteine, aspartic acid, glutamic        acid, phenylalanine, glycine, histidine, isoleucine, lysine,        leucine, methionine, asparagine, proline, glutamine, arginine,        serine, threonine, valine, tryptophan, or tyrosine;    -   AA5 is a bond, or glycine, valine, tyrosine, tryptophan,        phenylalanine, methionine, leucine, isoleucine, or asparagine;    -   AA₆ is a bond, or alanine, asparagine, citrulline, glutamine,        glycine, leucine, methionine, phenylalanine, serine, threonine,        tryptophan, tyrosine, valine, or H₂N(CH₂)_(m)CO₂H, wherein m is        2, 3, 4 or 5;    -   L is —OH, —O-succinimide, —O-sulfosuccinimide, alkoxy, aryloxy,        acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, —NH₂,        —NH(C₂-C₆ hydroxyalkyl), halide or perfluoroalkyloxy;    -   Q is NR, O, or S;    -   X is M-(C(R)₂)_(p)-M-J-M-(C(R)₂)_(p)-M-V;    -   M is a bond, or C(O);    -   J is a bond, or ((CH₂)_(q)Q)_(r), C₅-C₈ cycloalkyl, aryl,        heteroaryl, NR, O, or S;    -   Y is NR, O, or S;    -   R is H or alkyl;    -   V is a bond or

-   -   R⁹ is alkyl, aryl, aralkyl, or a bond; or R⁹ taken together with        Y forms a heterocyclic ring;    -   R¹⁰ is amido or a bond;    -   R¹¹ is H or alkyl;    -   W is a MetAP2 inhibitor moiety or alkyl;    -   x is in the range of 1 to about 450;    -   y is in the range of 1 to about 30;    -   n is in the range of 1 to about 100;    -   p is 0 to 20;    -   q is 2 or 3;    -   r is 1, 2, 3, 4, 5, or 6;        or a pharmaceutically acceptable salt, prodrug, metabolite,        analog or derivative thereof, wherein the subject has a        metabolic dysfunction, and wherein the cancer is treated.

In one aspect, the present disclosure least one compound, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, has the Formula:

The present disclosure also provides a method for treating, orameliorating at least one symptom of, cancer or treating ametabolically-sensitive tumor in a subject in need thereof comprisingadministering a therapeutically effective amount of at least onecompound, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof, represented by: Z-Q-X—Y—C(O)—W

wherein, independently for each occurrence,

Z is —H, —H₂N-AA₃-AA₄-AA₅-AA₆-C(O)— or Z is H₂N-AA₅-AA₆-C(O);

-   -   AA₃ is a bond, or alanine, cysteine, aspartic acid, glutamic        acid, phenylalanine, glycine, histidine, isoleucine, lysine,        leucine, methionine, asparagine, proline, glutamine, arginine,        serine, threonine, valine, tryptophan, or tyrosine;    -   AA₄ is a bond, or alanine, cysteine, aspartic acid, glutamic        acid, phenylalanine, glycine, histidine, isoleucine, lysine,        leucine, methionine, asparagine, proline, glutamine, arginine,        serine, threonine, valine, tryptophan, or tyrosine;    -   AA₅ is a bond, or glycine, valine, tyrosine, tryptophan,        phenylalanine, methionine, leucine, isoleucine, or asparagine;    -   AA₆ is alanine, asparagine, citrulline, glutamine, glycine,        leucine, methionine, phenylalanine, serine, threonine,        tryptophan, tyrosine, valine or H₂N(CH₂)mCO₂H, wherein m is 2,        3, 4 or 5;

Q is NR, O, or S;

X is M-(C(R)₂)_(p)-M-J-M-(C(R)₂)_(p)-M-V;

M is a bond, or C(O);

J is a bond, or ((CH₂)_(q)Q)_(r), C₅-C₈ cycloalkyl, aryl, heteroaryl,NR, O, or S;

Y is NR, O, or S;

R is H or alkyl;

V is a bond or

R⁹ is alkyl, aryl, aralkyl, or a bond; or R⁹ taken together with Y formsa heterocyclic ring;

R¹⁰ is amido or a bond;

R¹¹ is H or alkyl;

W is a MetAP2 inhibitor moiety;

p is 0 to 20;

q is 2 or 3; and

r is 1, 2, 3, 4, 5, or 6.

wherein the subject has a metabolic dysfunction, and wherein the canceris treated.

The cancer can be post-menopausal HR+/Her2− breast cancer, castrationresistant prostate cancer, esophageal carcinoma, colorectaladenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer,pancreatic adenocarcinoma, gall bladder cancer, liver cancer, clear-cellrenal cancer, melanoma, multiple myeloma, or combinations thereof.

The metabolic dysfunction can be excessive visceral adiposity, elevatedleptin levels, depressed adiponectin levels, high leptin-to-adiponectinratio, elevated fasting insulin levels accompanied by chronicinflammation, or combinations thereof.

The methods of the present disclosure can further including treating, orameliorating at least one symptom of, the metabolic dysfunction in saidsubject. The methods of the present disclosure can further includingincreasing adiponectin, decreasing leptin, decreasing fasting insulin,or combinations thereof in said subject.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, suitable methods and materials are described below.All publications, patent applications, patents and other referencesmentioned herein are incorporated by reference in their entirety for allpurposes. The references cited herein are not admitted to be prior artto the claimed disclosure. In the case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods and examples are illustrative only and are notintended to be limiting.

Other features and advantages of the disclosure will be apparent fromthe following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a graph baseline body weight in mice on a high-fat dietcompared to a low-fat diet.

FIG. 1B is a graph showing tumor growth in mice on a high-fat dietcompared to a low-fat diet.

FIG. 2A is a graph showing tumor inhibition in lean mice followingadministration of compounds of the present disclosure.

FIG. 2B is a graph showing tumor inhibition in obese mice followingadministration of compounds of the present disclosure.

FIG. 2C is a graph showing the percentage of tumor inhibition relativeto vehicle in lean mice versus obese mice following administration ofcompounds of the present disclosure.

FIG. 3A is a graph showing reduction in body weight of lean micefollowing administration of compounds of the present disclosure.

FIG. 3B is a graph showing reduction in body weight of obese micefollowing administration of compounds of the present disclosure.

FIG. 4 is a graph showing the relationship between body weight and tumorsize in lean mice and obese mice following administration of compoundsof the present disclosure.

FIG. 5 is a graph showing a reduction in the number of lung metastasesin lean mice and obese mice following administration of compounds of thepresent disclosure.

FIG. 6 is a graph showing a reduction in white blood cells in obesetumor-bearing mice following administration of compounds of the presentdisclosure.

FIG. 7 is a graph showing tumor growth inhibition in lean and obesetumor-bearing mice following administration of another MetAP2 inhibitor.

FIG. 8 is a graph showing decreased body weight in lean and obesetumor-bearing mice following administration of compounds of the presentdisclosure when compared to another MetAP2 inhibitor.

FIG. 9A is a graph showing a reduction in serum leptin in obesenon-tumor-bearing mice following administration of compounds of thepresent disclosure.

FIG. 9B is a graph showing an increase in serum adiponectin in obesenon-tumor-bearing mice following administration of compounds of thepresent disclosure.

FIG. 9C is a graph showing the ratio of leptin to adiponectin levels inobese non-tumor-bearing mice following administration of compounds ofthe present disclosure.

FIG. 9D is a graph showing serum adiponectin levels in obesetumor-bearing mice following administration of compounds of the presentdisclosure when compared to another MetAP2 inhibitor.

FIG. 10A is a graph showing reduced tumor growth in lean mammarytumor-bearing mice following administration of compounds of the presentdisclosure.

FIG. 10B is a graph showing reduced tumor growth in obese mammarytumor-bearing mice following administration of compounds of the presentdisclosure.

FIG. 11A is a graph showing reduced body weight in lean mammarytumor-bearing mice following administration of compounds of the presentdisclosure.

FIG. 11B is a graph showing body weight change relative to baseline inlean mammary tumor-bearing mice following administration of compounds ofthe present disclosure.

FIG. 11C is a graph showing reduced body weight in obese mammarytumor-bearing mice following administration of compounds of the presentdisclosure.

FIG. 11D is a graph showing body weight change relative to baseline inobese mammary tumor-bearing mice following administration of compoundsof the present disclosure.

FIG. 12A is a graph showing absolute values of various metabolicbiomarkers in the serum of a patient with carcinoid tumors followingadministration of compounds of the present disclosure.

FIG. 12B is a graph showing the percentage change relative to baselineof various metabolic biomarkers in the serum of a patient with carcinoidtumors following administration of compounds of the present disclosure.

FIG. 13A is a graph showing absolute values of various metabolicbiomarkers in the serum of a patient with colon cancer followingadministration of compounds of the present disclosure.

FIG. 13B is a graph showing the percentage change relative to baselineof various metabolic biomarkers in the serum of a patient with coloncancer following administration of compounds of the present disclosure.

FIG. 14A is a graph showing absolute values of various metabolicbiomarkers in the serum of a patient with endometrial cancer followingadministration of compounds of the present disclosure.

FIG. 14B is a graph showing the percentage change relative to baselineof various metabolic biomarkers in the serum of a patient withendometrial cancer following administration of compounds of the presentdisclosure.

FIG. 15A is a graph showing absolute values of various metabolicbiomarkers in the serum of a patient with cervical cancer followingadministration of compounds of the present disclosure.

FIG. 15B is a graph showing the percentage change relative to baselineof various metabolic biomarkers in the serum of a patient with cervicalcancer following administration of compounds of the present disclosure.

FIG. 16A is a graph showing absolute values of leptin in the serum of apatient with hormone receptor-positive breast cancer followingadministration of compounds of the present disclosure.

FIG. 16B is a graph showing the percentage change relative to baselineof leptin in the serum of a patient with hormone receptor-positivebreast cancer following administration of compounds of the presentdisclosure.

DETAILED DESCRIPTION OF THE DISCLOSURE Methods of Use

The present disclosure provides methods of treating, or ameliorating atleast one symptom of, a proliferation disorder in a subject in needthereof, comprising administering at least one MetAP2 inhibitor in atherapeutically effective amount to the subject to treat theproliferation disorder, wherein the subject has a metabolic dysfunction.In a preferred aspect, the proliferation disorder is cancer. The cancercan be post-menopausal HR+/Her2− breast cancer, castration resistantprostate cancer, esophageal carcinoma, colorectal adenocarcinoma,cervical cancer, endometrial cancer, ovarian cancer, pancreaticadenocarcinoma, gall bladder cancer, liver cancer, clear-cell renalcancer, melanoma, multiple myeloma, or combinations thereof Themetabolic dysfunction can include excessive visceral adiposity, elevatedleptin levels, depressed adiponectin levels, high leptin-to-adiponectinratio, elevated fasting insulin levels accompanied by chronicinflammation, or combinations thereof. Preferably, the metabolicdysfunction is low adiponectin, elevated leptin, elevated fastinginsulin, or combinations thereof The methods of the present disclosurecan also include treating, or ameliorating at least one symptom of, themetabolic dysfunction in addition to treating, or ameliorating at leastone symptom of, the proliferation disorder.

The present disclosure also provides methods of treating, orameliorating at least one symptom of, a proliferation disorder in asubject in need thereof, comprising administering at least onefumagillin analog or derivative in a therapeutically effective amount tothe subject to treat the proliferation disorder, wherein the subject hasa metabolic dysfunction. In a preferred aspect, the proliferationdisorder is cancer. The cancer can be post-menopausal HR+/Her2− breastcancer, castration resistant prostate cancer, esophageal carcinoma,colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovariancancer, pancreatic adenocarcinoma, gall bladder cancer, liver cancer,clear-cell renal cancer, melanoma, multiple myeloma, or combinationsthereof The metabolic dysfunction can include excessive visceraladiposity, elevated leptin levels, depressed adiponectin levels, highleptin-to-adiponectin ratio, elevated fasting insulin levels accompaniedby chronic inflammation, or combinations thereof Preferably, themetabolic dysfunction is low adiponectin, elevated leptin, elevatedfasting insulin, or combinations thereof The methods of the presentdisclosure can also include treating, or ameliorating at least onesymptom of, the metabolic dysfunction in addition to treating, orameliorating at least one symptom of, the proliferation disorder.

The present disclosure also provides methods of treating, orameliorating at least one symptom of, a proliferation disorder in asubject in need thereof, comprising administering at least one compoundof the present disclosure in a therapeutically effective amount to thesubject to treat the proliferation disorder, wherein the subject has ametabolic dysfunction. In a preferred aspect, the proliferation disorderis cancer. The cancer can be post-menopausal HR+/Her2− breast cancer,castration resistant prostate cancer, esophageal carcinoma, colorectaladenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer,pancreatic adenocarcinoma, gall bladder cancer, liver cancer, clear-cellrenal cancer, melanoma, multiple myeloma, or combinations thereof Themetabolic dysfunction can include excessive visceral adiposity, elevatedleptin levels, depressed adiponectin levels, high leptin-to-adiponectinratio, elevated fasting insulin levels accompanied by chronicinflammation, or combinations thereof. Preferably, the metabolicdysfunction is low adiponectin, elevated leptin, elevated fastinginsulin, or combinations thereof. The methods of the present disclosurecan also include treating, or ameliorating at least one symptom of, themetabolic dysfunction in addition to treating, or ameliorating at leastone symptom of, the proliferation disorder.

The present disclosure also provides methods of treating ametabolically-sensitive tumor in a subject in need thereof comprisingadministering at least one MetAP2 inhibitor in a therapeuticallyeffective amount to the subject to treat the metabolically-sensitivetumors, wherein the subject has a metabolic dysfunction. Themetabolically-sensitive tumor can be the result of post-menopausalHR+/Her2− breast cancer, castration resistant prostate cancer,esophageal carcinoma, colorectal adenocarcinoma, cervical cancer,endometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, liver cancer, clear-cell renal cancer, melanoma,multiple myeloma, or combinations thereof The metabolic dysfunction caninclude excessive visceral adiposity, elevated leptin levels, depressedadiponectin levels, high leptin-to-adiponectin ratio, elevated fastinginsulin levels accompanied by chronic inflammation, or combinationsthereof. Preferably, the metabolic dysfunction is low adiponectin,elevated leptin, elevated fasting insulin, or combinations thereof. Themethods of the present disclosure can also include treating, orameliorating at least one symptom of, the metabolic dysfunction inaddition to treating the metabolically-sensitive tumor.

The present disclosure also provides methods of treating ametabolically-sensitive tumor in a subject in need thereof comprisingadministering at least one fumagillin analog or derivative in atherapeutically effective amount to the subject to treat themetabolically-sensitive tumor, wherein the subject has a metabolicdysfunction. The metabolically-sensitive tumor can be the result ofpost-menopausal HR+/Her2− breast cancer, castration resistant prostatecancer, esophageal carcinoma, colorectal adenocarcinoma, cervicalcancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma,gall bladder cancer, liver cancer, clear-cell renal cancer, melanoma,multiple myeloma, or combinations thereof The metabolic dysfunction caninclude excessive visceral adiposity, elevated leptin levels, depressedadiponectin levels, high leptin-to-adiponectin ratio, elevated fastinginsulin levels accompanied by chronic inflammation, or combinationsthereof. Preferably, the metabolic dysfunction is low adiponectin,elevated leptin, elevated fasting insulin, or combinations thereof Themethods of the present disclosure can also include treating, orameliorating at least one symptom of, the metabolic dysfunction inaddition to treating the metabolically-sensitive tumor.

The present disclosure also provides methods of treating ametabolically-sensitive tumor in a subject in need thereof comprisingadministering at least one compound of the present disclosure in atherapeutically effective amount to the subject to treat themetabolically-sensitive tumor, wherein the subject has a metabolicdysfunction. The metabolically-sensitive tumor can be the result ofpost-menopausal HR+/Her2− breast cancer, castration resistant prostatecancer, esophageal carcinoma, colorectal adenocarcinoma, cervicalcancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma,gall bladder cancer, liver cancer, clear-cell renal cancer, melanoma,multiple myeloma, or combinations thereof The metabolic dysfunction caninclude excessive visceral adiposity, elevated leptin levels, depressedadiponectin levels, high leptin-to-adiponectin ratio, elevated fastinginsulin levels accompanied by chronic inflammation, or combinationsthereof. Preferably, the metabolic dysfunction is low adiponectin,elevated leptin, elevated fasting insulin, or combinations thereof Themethods of the present disclosure can also include treating, orameliorating at least one symptom of, the metabolic dysfunction inaddition to treating the metabolically-sensitive tumor.

Obesity has been identified as a risk factor for postmenopausal breastcancer and excess visceral adipose tissue is associated with a worseresponse to chemotherapy and reduced progression and/or disease-freesurvival (Schaffler, A., et al. (2007) Nat Clin Pract Endocrinol Metab3:345-54; Vona-Davis, L. Rose, D P. (2007) Endocr Relat Cancer14:189-206). Adipose tissue-derived factors (e.g. leptin, adiponectin,aromatase, IL-6) have been proposed as possible mediators of theobesity-breast cancer link, and recent data draw attention specificallyto the adipokines leptin and adiponectin (Cleary, M P., et al. (2009)Front Biosci (School Ed) 1:329-57; Cleary, M P., et al. (2010) VetPathol 47:202-13). The molecular basis for underlying the role ofleptin, adiponectin and other hormones, such as insulin and insulin-lifegrowth factors have recently been described. Circulating adiponectinlevels are inversely correlated with body mass index (BMI); in contrast,serum leptin positively correlates with BMI (Ryan, A S., et al. (2003)Diabetes Care 26:2383-8; Wauters, M., et al. (2000) Eur J Endocrinol143:293-311). In obese individuals, especially in those with highvisceral fat content, adiponectin levels are depressed (Brochu-GaudreauK, et al. Endocrine 2010, 37(1):11-32). Adiponectin is found in humanserum at concentrations of 2-20 μg/ml (Grossmann, M E., et al. (2008) BrJ Cancer 98:370-9). The mechanism underlying adiponectin signaling andcancer prevention is thought to involve the activation of intracellularsignals AMPK and inhibition of growth and survival pathways(Brochu-Gaudreau K, et al. Endocrine 2010, 37(1):11-32, Pfeiler G etal., Maturitas 2009, 63(3):253-256). Further, adiponectin may exert itsbiological activity indirectly, through selective sequestration ofdifferent growth factors (e.g., basic fibroblast growth factor,platelet-derived growth factor BB, heparin-binding epidermal growthfactor) and inhibition of their normal receptor binding. Theseinteractions involve specific oligomeric forms of adiponectin. Barb, D.,Williams, C J., Neuwirth, A K., Mantzoros, C S. (2007) Am J Clin Nutr86:s858-66. Wang et al. (2005) J Biol Chem 280:18341-7).

Several epidemiological studies found an inverse relation betweenadiponectin levels and breast cancer risk (Barb, et al. (2007) Am J ClinNutr 86:s858-66; Miyoshi, et al. (2003) Clin Cancer Res 9:5699-704.Mantzoros, et al. (2004) J Clin Endocrinol Metab 89:1102-7; Chen, D C.,et al. (2006) Cancer Lett 237:109-14). In breast cancer patients, theadiponectin levels and the adiponectin-to-leptin ratio tend to bereduced relative to that found in lean women (Cleary M P., et al.,(2009) Front Biosci (Schol Ed) 1:329-57; Cleary, M P., et al. (2006)Cancer Lett 237:109-14). Breast cancer patients with low adiponectinlevels are reported to have more aggressive tumors and higher frequencyof lymph node metastasis (Schaffler, A., et al. (2007) Nat Clin PractEndocrinol Metab 3:345-54; Hou, W K., et al. (2007) Chin Med J (Engl)120:1592-6).

In one aspect, the present disclosure provides methods of utilizing atleast one MetAP2 inhibitor, at least one fumagillin analog or derivativeand/or at least one compound of the present disclosure to treat specifictumor types that are exacerbated by metabolic dysfunction, includingpost-menopausal HR+/Her2− breast cancer, castration resistant prostatecancer, esophageal carcinoma, colorectal adenocarcinoma, cervicalcancer, endometrial cancer, ovarian cancer, pancreatic adenocarcinoma,gall bladder cancer, liver cancer, clear-cell renal cancer, melanoma,multiple myeloma, or combinations thereof. In preferred aspects, thepresent methods disclose subcutaneous administration of an MetAP2inhibitor in cancer patients with metabolic dysfunction. The metabolicdysfunction can include excessive visceral adiposity, elevated leptinlevels, depressed adiponectin levels, high leptin-to-adiponectin ratio,elevated fasting insulin levels accompanied by chronic inflammation, orcombinations thereof The present methods can restore the patient to amore metabolically neutral and stable state and slow or reverse theprogression of the patient's cancer.

Described herein are methods to improve the underlying metabolicdysfunction in patients with metabolically-sensitive tumors. The methodsof treating the metabolically-sensitive tumors include increasing thelevels of adiponectin, lowering the levels of leptin, improving theleptin-to-adiponectin ratio, or combinations thereof. Subcutaneousadministration of the MetAP2 inhibitors described herein havedemonstrated the ability to improve these levels and ratios in cancerpatients, and thus, can be used for the treatment of metabolicallysensitive tumors which can benefit from an adiponectin upregulationalong with improved leptin sensitivity. Accordingly, in certain aspects,the MetAP2 inhibitors described herein can treat cancers includingpost-menopausal hormone-receptor positive (HR+) breast cancer,castration resistant prostate cancer, esophageal adenocarcinoma,colorectal adenocarcinoma, cervical cancer, endometrial cancer, ovariancancer, pancreatic adenocarcinoma, gall bladder, hepatocellularcarcinoma, clear-cell renal cancer, melanoma, multiple myeloma, orcombinations thereof The aforementioned cancers can be related to, atleast in part, to adiponectin deficiency and/or adiponectin resistance.

The present disclosure also provides methods of treating cancer in asubject in need thereof, said method comprising the steps of (i)identifying the patient as having post-menopausal hormone-receptorpositive (HR+) breast cancer, castration resistant prostate cancer,esophageal adenocarcinoma, colorectal adenocarcinoma, cervical, cancerendometrial cancer, ovarian cancer, pancreatic adenocarcinoma, gallbladder cancer, hepatocellular carcinoma, clear-cell renal cancer,melanoma, multiple myeloma, or a combination thereof; (ii) determiningwhether the cancer patient has metabolic dysfunction, and (iii) if thesubject is identified as having one of the cancers in step (i) andmetabolic dysfunction in step (ii), administering a therapeuticallyeffective amount of at least one MetAP2 inhibitor, at least onefumagillin analog or derivative, or at least one compound of the presentdisclosure. Preferably, the subject is administered a compound of thepresent disclosure. Preferably, the compound is administeredsubcutaneously. The metabolic dysfunction can include excessive visceraladiposity, elevated leptin levels, depressed adiponectin levels, highleptin-to-adiponectin ratio, elevated fasting insulin levels accompaniedby chronic inflammation, or combinations thereof. Preferably, themetabolic dysfunction is low adiponectin, elevated leptin, elevatedfasting insulin, or combinations thereof The methods of the presentdisclosure can also include treating, or ameliorating at least onesymptom of, the metabolic dysfunction in addition to treating thecancer.

In another aspect, the present disclosure provides a method ofdetermining whether a tumor is metabolically sensitive and comprising:(1) measuring the level of fasting insulin and glucose to determine theHOMA score (insulin sensitivity level) for the patient, (2) comparingthe HOMA score to that of lean patients, and (3) determining that, ifthe level of the HOMA score is larger than the metabolically normallevel, the cancer is susceptible to treatment with at least one MetAP2inhibitor, at least one fumagillin analog or derivative, or at least onecompound of the present disclosure.

As used herein, a “subject in need thereof” is a subject having a cellproliferative disorder, or a subject having an increased risk ofdeveloping a cell proliferative disorder relative to the population atlarge. A subject in need thereof can have a precancerous condition.Preferably, a subject in need thereof has cancer. Preferably, thesubject having a cell proliferative disorder also has metabolicdysfunction.

A “subject” includes a mammal. The mammal can be e.g., any mammal, e.g.,a human, primate, bird, mouse, rat, fowl, dog, cat, cow, horse, goat,rabbit, camel, sheep or a pig. Preferably, the mammal is a human. Theterm “subject” and “patient” are used interchangeably herein.

As used herein, the term “cell proliferative disorder” refers toconditions in which unregulated or abnormal growth, or both, of cellscan lead to the development of an unwanted condition or disease, whichmay or may not be cancerous. Exemplary cell proliferative disorders ofthe disclosure encompass a variety of conditions wherein cell divisionis deregulated. Exemplary cell proliferative disorder include, but arenot limited to, neoplasms, benign tumors, malignant tumors,pre-cancerous conditions, in situ tumors, encapsulated tumors,metastatic tumors, liquid tumors, solid tumors, immunological tumors,hematological tumors, cancers, carcinomas, leukemias, lymphomas,sarcomas, and rapidly dividing cells. The term “rapidly dividing cell”as used herein is defined as any cell that divides at a rate thatexceeds or is greater than what is expected or observed amongneighboring or juxtaposed cells within the same tissue. A cellproliferative disorder includes a precancer or a precancerous condition.A cell proliferative disorder includes cancer. A cell proliferativedisorder includes a non-cancer condition or disorder. Preferably, themethods provided herein are used to treat or alleviate a symptom ofcancer. The term “cancer” includes solid tumors, as well as, hematologictumors and/or malignancies. A “precancer cell” or “precancerous cell” isa cell manifesting a cell proliferative disorder that is a precancer ora precancerous condition. A “cancer cell” or “cancerous cell” is a cellmanifesting a cell proliferative disorder that is a cancer. Anyreproducible means of measurement may be used to identify cancer cellsor precancerous cells. Cancer cells or precancerous cells can beidentified by histological typing or grading of a tissue sample (e.g., abiopsy sample). Cancer cells or precancerous cells can be identifiedthrough the use of appropriate molecular markers.

Exemplary non-cancerous conditions or disorders include, but are notlimited to, rheumatoid arthritis; inflammation; autoimmune disease;lymphoproliferative conditions; acromegaly; rheumatoid spondylitis;osteoarthritis; gout, other arthritic conditions; sepsis; septic shock;endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma;adult respiratory distress syndrome; chronic obstructive pulmonarydisease; chronic pulmonary inflammation; inflammatory bowel disease;Crohn's disease; skin-related hyperproliferative disorders, psoriasis;eczema; atopic dermatitis; hyperpigmentation disorders, eye-relatedhyperproliferative disorders, age-related macular degeneration,ulcerative colitis; pancreatic fibrosis; hepatic fibrosis; acute andchronic renal disease; irritable bowel syndrome; pyresis; restenosis;cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer'sdisease; Huntington's disease; Parkinson's disease; acute and chronicpain; allergic rhinitis; allergic conjunctivitis; chronic heart failure;acute coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lymedisease; Reiter's syndrome; acute synovitis; muscle degeneration,bursitis; tendonitis; tenosynovitis; herniated, ruptures, or prolapsedintervertebral disk syndrome; osteopetrosis; thrombosis; restenosis;silicosis; pulmonary sarcosis; bone resorption diseases, such asosteoporosis; graft-versus-host reaction; fibroadipose hyperplasia;spinocerebullar ataxia type 1; CLOVES syndrome; Harlequin ichthyosis;macrodactyly syndrome; Proteus syndrome (Wiedemann syndrome); LEOPARDsyndrome; systemic sclerosis; Multiple Sclerosis; lupus; fibromyalgia;AIDS and other viral diseases such as Herpes Zoster, Herpes Simplex I orII, influenza virus and cytomegalovirus; diabetes mellitus;hemihyperplasia-multiple lipomatosis syndrome; megalencephaly; rarehypoglycemia, Klippel-Trenaunay syndrome; harmatoma; Cowden syndrome; orovergrowth-hyperglycemia.

Exemplary cancers include, but are not limited to, adrenocorticalcarcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer,anorectal cancer, cancer of the anal canal, anal squamous cellcarcinoma, angiosarcoma, appendix cancer, childhood cerebellarastrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skincancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer,intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer,bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma,brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma,cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma,supratentorial primitive neuroectodeimal tumors, visual pathway andhypothalamic glioma, breast cancer, bronchial adenomas/carcinoids,carcinoid tumor, gastrointestinal, nervous system cancer, nervous systemlymphoma, central nervous system cancer, central nervous systemlymphoma, cervical cancer, childhood cancers, chronic lymphocyticleukemia, chronic myelogenous leukemia, chronic myeloproliferativedisorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma,lymphoid neoplasm, mycosis fungoides, Seziary Syndrome, endometrialcancer, esophageal cancer, extracranial germ cell tumor, extragonadalgerm cell tumor, extrahepatic bile duct cancer, eye cancer, intraocularmelanoma, retinoblastoma, gallbladder cancer, gastric (stomach) cancer,gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST),germ cell tumor, ovarian germ cell tumor, gestational trophoblastictumor glioma, head and neck cancer, head and neck squamous cellcarcinoma, hepatocellular (liver) cancer, Hodgkin lymphoma,hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet celltumors (endocrine pancreas), Kaposi Sarcoma, kidney cancer, renalcancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia,T-cell lymphoblastic leukemia, acute myeloid leukemia, chroniclymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia,lip and oral cavity cancer, liver cancer, lung cancer, non-small celllung cancer, small cell lung cancer, lung squamous cell carcinoma,AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervoussystem lymphoma, B-cell lymphoma, primary effusion lymphoma, Waldenstrammacroglobulinemia, medulloblastoma, melanoma, intraocular (eye)melanoma, merkel cell carcinoma, mesothelioma malignant, mesothelioma,metastatic squamous neck cancer, mouth cancer, cancer of the tongue,multiple endocrine neoplasia syndrome, mycosis fungoides,myelodysplastic syndromes, myelodysplastic/myeloproliferative diseases,chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma,chronic myeloproliferative disorders, nasopharyngeal cancer,neuroblastoma, oral cancer, oral cavity cancer, oropharyngeal cancer,ovarian cancer, ovarian epithelial cancer, ovarian low malignantpotential tumor, pancreatic cancer, islet cell pancreatic cancer,pancreatic endocrine tumor, paranasal sinus and nasal cavity cancer,parathyroid cancer, cholangiocarcinoma, penile cancer, pharyngealcancer, pheochromocytoma, pineoblastoma and supratentorial primitiveneuroectodermal tumors, pituitary tumor, pituitary adenoma, plasma cellneoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer,rectal cancer, renal pelvis and ureter, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Ewing family ofsarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterine cancer,uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma),merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma,squamous cell carcinoma, stomach (gastric) cancer, supratentorialprimitive neuroectodermal tumors, testicular cancer, throat cancer,thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter and other urinary organs,gestational trophoblastic tumor, urethral cancer, endometrial uterinecancer, uterine sarcoma, uterine corpus cancer, vaginal cancer, vulvarcancer, and Wilm's Tumor.

A “cell proliferative disorder of the hematologic system” is a cellproliferative disorder involving cells of the hematologic system. A cellproliferative disorder of the hematologic system can include lymphoma,leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benignmonoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoidpapulosis, polycythemia vera, chronic myelocytic leukemia, agnogenicmyeloid metaplasia, and essential thrombocythemia. A cell proliferativedisorder of the hematologic system can include hyperplasia, dysplasia,and metaplasia of cells of the hematologic system. Preferably,compositions of the present disclosure can be used to treat a cancerselected from the group consisting of a hematologic cancer of thepresent disclosure or a hematologic cell proliferative disorder of thepresent disclosure. A hematologic cancer of the present disclosure caninclude multiple myeloma, lymphoma (including Hodgkin's lymphoma,non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas oflymphocytic and cutaneous origin), leukemia (including childhoodleukemia, hairy-cell leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia, chronic lymphocytic leukemia, chronic myelocyticleukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloidneoplasms and mast cell neoplasms.

A cancer that is to be treated can be staged according to the AmericanJoint Committee on Cancer (AJCC) TNM classification system, where thetumor (T) has been assigned a stage of TX, T1, T1mic, T1a, T1b, T1c, T2,T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N)have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, orN3c; and where distant metastasis (M) can be assigned a stage of MX, M0,or M1. A cancer that is to be treated can be staged according to anAmerican Joint Committee on Cancer (AJCC) classification as Stage I,Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. Acancer that is to be treated can be assigned a grade according to anAJCC classification as Grade GX (e.g., grade cannot be assessed), Grade1, Grade 2, Grade 3 or Grade 4. A cancer that is to be treated can bestaged according to an AJCC pathologic classification (pN) of pNX, pN0,PN0 (I−), PNO (I+), PN0 (mol−), PN0 (mol+), PN1, PN1(mi), PN1a, PN1b,PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

A cancer that is to be treated can include a tumor that has beendetermined to be less than or equal to about 2 centimeters in diameter.A cancer that is to be treated can include a tumor that has beendetermined to be from about 2 to about 5 centimeters in diameter. Acancer that is to be treated can include a tumor that has beendetermined to be greater than or equal to about 3 centimeters indiameter. A cancer that is to be treated can include a tumor that hasbeen determined to be greater than 5 centimeters in diameter. A cancerthat is to be treated can be classified by microscopic appearance aswell differentiated, moderately differentiated, poorly differentiated,or undifferentiated. A cancer that is to be treated can be classified bymicroscopic appearance with respect to mitosis count (e.g., amount ofcell division) or nuclear pleiomorphism (e.g., change in cells). Acancer that is to be treated can be classified by microscopic appearanceas being associated with areas of necrosis (e.g., areas of dying ordegenerating cells). A cancer that is to be treated can be classified ashaving an abnormal karyotype, having an abnormal number of chromosomes,or having one or more chromosomes that are abnormal in appearance. Acancer that is to be treated can be classified as being aneuploid,triploid, tetraploid, or as having an altered ploidy. A cancer that isto be treated can be classified as having a chromosomal translocation,or a deletion or duplication of an entire chromosome, or a region ofdeletion, duplication or amplification of a portion of a chromosome.

A cancer that is to be treated can be evaluated by DNA cytometry, flowcytometry, or image cytometry. A cancer that is to be treated can betyped as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cellsin the synthesis stage of cell division (e.g., in S phase of celldivision). A cancer that is to be treated can be typed as having a lowS-phase fraction or a high S-phase fraction.

As used herein, a “normal cell” is a cell that cannot be classified aspart of a “cell proliferative disorder”. A normal cell lacks unregulatedor abnormal growth, or both, that can lead to the development of anunwanted condition or disease. Preferably, a normal cell possessesnormally functioning cell cycle checkpoint control mechanisms.

As used herein, “contacting a cell” refers to a condition in which acompound or other composition of matter of the present disclosure is indirect contact with a cell, or is close enough to induce a desiredbiological effect in a cell.

In addition to treating or alleviating at least one symptom of one ormore proliferation disorders, the compounds of the present disclosurecan also treat or alleviate a variety of related disorders.

In particular, addition to treating or alleviating at least one symptomof one or more proliferation disorders, the compounds of the presentdisclosure can also treat or alleviate at least one metabolicdysfunction selected from the group consisting of excessive visceraladiposity, elevated leptin levels, depressed adiponectin levels, highleptin-to-adiponectin ratio, elevated fasting insulin levels accompaniedby chronic inflammation, or combinations thereof. Preferably, themetabolic dysfunction that is treated or ameliorated is low adiponectin,elevated leptin, elevated fasting insulin, or combinations thereof

In addition to treating or alleviating at least one symptom of one ormore proliferation disorders, the compounds of the present disclosurecan also treat or alleviate at least one symptom of obesity.

In addition to treating or alleviating at least one symptom of one ormore proliferation disorders, the compounds of the present disclosurecan also decrease body weight. In certain aspects, the subject isoverweight or obese. In certain aspects, the subject is in need ofreducing excess adipose tissue.

Obesity and being overweight refer to an excess of fat in a subject inproportion to lean body mass. Excess fat accumulation is associated withan increase in size (hypertrophy or steatosis) as well as number(hyperplasia) of adipose tissue cells. Obesity can be due to any cause,whether genetic (e.g. Prader-Willi Syndrome) or environmental. Obesityis variously measured in terms of absolute weight, weight:height ratio,degree of excess body fat, distribution of visceral or subcutaneous fat,and societal and esthetic norms. A common measure of body fat is BodyMass Index (BMI). The BMI refers to the ratio of body weight (expressedin kilograms) to the square of height (expressed in meters). Body massindex can be accurately calculated using the formulas: SI units:BMI=weight(kg)/(height²(m²), or US units:BMI=(weight(b)*703)/(height²(in²).

As described herein, “overweight” refers to a condition whereby anotherwise healthy adult that has a BMI of 25 kg/m² to 29.9 kg/m². Asdescribed herein, “obese” or “obesity” refers to a condition whereby anotherwise healthy adult that has a BMI of 30 kg/m² or greater. Obesityhas several subcategories. An adult that has a BMI of 35 kg/m² orgreater is referred to as “severely obese” or “severe obesity”. An adultthat has a BMI of ≧40-44.9 kg/m² or and adult that has a BMI of 35 kg/m²or greater and at least one obesity-related health condition is referredto as “morbidly obese” or “morbid obesity”. An adult that has a BMI of45 kg/m² or greater is referred to as “super obese” or “super obesity”.For children, the definitions of overweight and obese take into accountage and gender effects on body fat.

Different countries can define obesity and overweight with differentBMI. The term “obesity” is meant to encompass definitions in allcountries. For example, the increased risks associated with obesityoccur at a lower Body Mass Index (BMI) in Asians. In Asian countries,including Japan, “obesity” refers to a condition whereby a subject withat least one obesity-induced or obesity-related co-morbidity, thatrequires weight reduction or that would be improved by weight reduction,has a BMI greater than or equal to 25.0 kg/m². Ethnic South and CentralAmericans tend to be categorized more closely to Asians than Europeansor North Americans.

BMI does not account for the fact that excess adipose tissue can occurselectively in different parts of the body, and development of adiposetissue can be more dangerous to health in some parts of the body ratherthan in other parts of the body. For example, “central obesity”,typically associated with an “apple-shaped” body, results from excessadiposity especially in the abdominal region, including belly fat andvisceral fat, and carries higher risk of co-morbidity than “peripheralobesity”, which is typically associated with a “pear-shaped” bodyresulting from excess adiposity especially on the hips. Measurement ofwaist/hip circumference ratio (WHR) can be used as an indicator ofcentral obesity. A minimum WHR indicative of central obesity has beenvariously set, and a centrally obese adult typically has a WHR of about0.85 or greater if female and about 0.9 or greater if male.

Methods of determining whether a subject is overweight or obese thataccount for the ratio of excess adipose tissue to lean body mass caninvolve obtaining a body composition of the subject. Body compositioncan be obtained by measuring the thickness of subcutaneous fat inmultiple places on the body, such as the abdominal area, the subscapularregion, arms, buttocks and thighs. These measurements are then used toestimate total body fat with a margin of error of approximately fourpercentage points. Another method is bioelectrical impedance analysis(BIA), which uses the resistance of electrical flow through the body toestimate body fat. Another method is using a large tank of water tomeasure body buoyancy. Increased body fat will result in greaterbuoyancy, while greater muscle mass will result in a tendency to sink.Another method is fan-beam dual energy X-ray absorptiometry (DEXA). DEXAallows body composition, particularly total body fat and/or regional fatmass, to be determined non-invasively. MRI can also be used to determinecomposition non-invasively.

In addition to treating or alleviating at least one symptom of one ormore proliferation disorders, the compounds of the present disclosurecan also decrease adipocytes or adipose tissue. Decreasing adipocytesmeans decreasing the number or decreasing the size (fat content) of theadipocytes. In certain aspects, the compounds of the present disclosureshrink the adipocytes in the subject. The adipose tissue can be whiteadipose tissue or brown adipose tissue.

In addition to treating or alleviating at least one symptom of one ormore proliferation disorders, the compounds of the present disclosurecan also decrease food intake. A reduction in food intake means adecrease in daily food intake. A decrease in daily food intake can beabout a 5% decrease to about a 50% decrease (e.g., about 5%, about 10%,about 20%, about 30%, about 40% or about 50%). Based on a 2000 kcaldaily diet, the decrease is about 100 kcal to about 1000 kcal decreaseper day (e.g., about 100 kcal, about 200 kcal, about 400 kcal, about 600kcal, about 800 kcal or about 1000 kcal).

In addition to treating or alleviating at least one symptom of one ormore proliferation disorders, the compounds of the present disclosurecan also reduce a sense of hunger in a subject. The subject can alsohave a decrease in food intake. Sense of hunger can be assessed in afasted state using a 10-point visual analog scale (VAS), which is wellutilized in appetite research. See, Flint et al. Int. J. Obes. Relat.Metab. Disord. 24(1): 38-48, 2000. Specifically, subjects are asked torate their overall sense of hunger for the previous 2 days on a scale of1-10, where 10 was extremely hungry and 1 was not hungry at all.

In addition to treating or alleviating at least one symptom of one ormore proliferation disorders, the compounds of the present disclosurecan also decrease waist circumference. Waist circumference is assessedby using a tape measure placed around the abdomen 1 cm above the iliaccrest. The subjects of the present disclosure can have a decrease inwaist circumference from about 1 inch to about 20 inches (e.g., 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 inches).

In addition to treating or alleviating at least one symptom of one ormore proliferation disorders, the compounds of the present disclosurecan also decrease body fat and provide substantial maintenance of musclemass in said patient. In certain aspects, upon administration, fatoxidation is enhanced in a patient as compared to a patient on arestricted food intake diet alone. Such a patient can retainsubstantially more muscle mass as compared to body fat reduction in apatient using an energy restricted diet alone.

In addition to treating or alleviating at least one symptom of one ormore proliferation disorders, the compounds of the present disclosurecan also lower insulin levels, leptin levels or both in the subject. Incertain aspects, the subject is overweight or obese. In certain aspects,the subject is in need of reducing excess adipose tissue.

In addition to treating or alleviating at least one symptom of one ormore proliferation disorders, the compounds of the present disclosurecan also improve surgical outcome comprising administering, prior tosurgery, at least one compound of the present disclosure in atherapeutically effective amount to the subject to improve surgicaloutcome. In certain aspects, administration reduces liver and/orabdominal fat in said patient and improves surgical outcome. In certainaspects, the surgery is non-acute surgery. Such surgeries can includebariatric surgery, cardiovascular surgery, abdominal surgery, ororthopedic surgery.

As used herein, “monotherapy” refers to the administration of a singleactive or therapeutic compound of the present disclosure to a subject inneed thereof. For example, administering a cancer monotherapy with oneof the compounds of the present disclosure, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof, to asubject in need of treatment of cancer. Monotherapy can be contrastedwith combination therapy, in which a combination of multiple activecompounds is administered, as described below. In one aspect,monotherapy with a compound of the present disclosure, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, is more effective than combination therapy in inducinga desired biological effect.

As used herein, “combination therapy” or “co-therapy” includes theadministration of at least two compounds of the present disclosure, orpharmaceutically acceptable salts, prodrugs, metabolites, polymorphs orsolvates thereof, as part of a specific treatment regimen intended toprovide the beneficial effect from the co-action of these at least twocompounds of the present disclosure. The beneficial effect of thecombination includes, but is not limited to, pharmacokinetic orpharmacodynamic co-action resulting from the combination of these atleast two compounds of the present disclosure. Administration of theseat least two compounds of the present disclosure in combinationtypically is carried out over a defined time period (usually minutes,hours, days or weeks depending upon the combination selected).“Combination therapy” can be, but generally is not, intended toencompass the administration of two or more of these compounds of thepresent disclosure as part of separate monotherapy regimens thatincidentally and arbitrarily result in the combinations of the presentdisclosure.

“Combination therapy” also embraces the administration of the compoundsof the present disclosure in further combination with a second activeagent and/or non-drug therapy (e.g., surgery or radiation treatment).Where the combination therapy further comprises a non-drug treatment,the non-drug treatment can be conducted at any suitable time so long asa beneficial effect from the co-action of the combination of thetherapeutic agents and non-drug treatment is achieved. For example, inappropriate cases, the beneficial effect is still achieved when thenon-drug treatment is temporally removed from the administration of thetherapeutic agents, perhaps by days or even weeks. The second activeagent can be conjugated to a polymer.

“Combination therapy” is intended to embrace administration of thesetherapeutic agents in a sequential manner, wherein each therapeuticagent is administered at a different time, as well as administration ofthese therapeutic agents, or at least two of the therapeutic agents, ina substantially simultaneous manner. Substantially simultaneous manneras used herein is administration of the at least two therapeutic agentswithin 1 hour of each other. Substantially simultaneous administrationcan be accomplished, for example, by administering to the subject asingle composition having a fixed ratio of each therapeutic agent or inseparate capsules for each of the therapeutic agents. Sequential manneras used herein is administration of one of the at least two therapeuticagents more than one hour after the other of the at least twotherapeutic agents. Preferably, for sequential administration, one ofthe at least two therapeutic agents is administered at least 12 hours,at least 24 hours, at least 48 hours, at least 96 hours or at least oneweek after administration of the other therapeutic agent. Sequential orsubstantially simultaneous administration of each therapeutic agent canbe effected by any appropriate route including, but not limited to, oralroutes, intravenous routes, subcutaneous routes, intramuscular routes,and direct absorption through mucous membrane tissues. The therapeuticagents can be administered by the same route or by different routes. Forexample, a first therapeutic agent of the combination selected can beadministered by subcutaneous injection while the other therapeuticagents of the combination can be administered orally. Alternatively, forexample, all therapeutic agents can be administered orally or alltherapeutic agents can be administered by subcutaneous injection. Thesequence in which the therapeutic agents are administered is notnarrowly critical.

In a preferred aspect, the second active agent is a chemotherapeuticagent. The additional chemotherapeutic agent (also referred to as ananti-neoplastic agent or anti-proliferative agent) can be an alkylatingagent; an antibiotic; an anti-metabolite; a detoxifying agent; aninterferon; a polyclonal or monoclonal antibody; an EGFR inhibitor; anFGFR inhibitor, a HER2 inhibitor; a histone deacetylase inhibitor; ahormone; a mitotic inhibitor; an MTOR inhibitor; a multi-kinaseinhibitor; a serine/threonine kinase inhibitor; a tyrosine kinaseinhibitors; a VEGF/VEGFR inhibitor; a taxane or taxane derivative, anaromatase inhibitor, an anthracycline, a microtubule targeting drug, atopoisomerase poison drug, an inhibitor of a molecular target or enzyme(e.g., a kinase inhibitor), a cytidine analogue drug or anychemotherapeutic, anti-neoplastic or anti-proliferative agent listed inwww.cancer.org/docroot/cdg/cdg_0.asp.

Exemplary alkylating agents include, but are not limited to,cyclophosphamide (Cytoxan; Neosar); chlorambucil (Leukeran); melphalan(Alkeran); carmustine (BiCNU); busulfan (Busulfex); lomustine (CeeNU);dacarbazine (DTIC-Dome); oxaliplatin (Eloxatin); carmustine (Gliadel);ifosfamide (Ifex); mechlorethamine (Mustargen); busulfan (Myleran);carboplatin (Paraplatin); cisplatin (CDDP; Platinol); temozolomide(Temodar); thiotepa (Thioplex); bendamustine (Treanda); or streptozocin(Zanosar).

Exemplary antibiotics include, but are not limited to, doxorubicin(Adriamycin); doxorubicin liposomal (Doxil); mitoxantrone (Novantrone);bleomycin (Blenoxane); daunorubicin (Cerubidine); daunorubicin liposomal(DaunoXome); dactinomycin (Cosmegen); epirubicin (Ellence); idarubicin(Idamycin); plicamycin (Mithracin); mitomycin (Mutamycin); pentostatin(Nipent); or valrubicin (Valstar).

Exemplary anti-metabolites include, but are not limited to, fluorouracil(Adrucil); capecitabine (Xeloda); hydroxyurea (Hydrea); mercaptopurine(Purinethol); pemetrexed (Alimta); fludarabine (Fludara); nelarabine(Arranon); cladribine (Cladribine Novaplus); clofarabine (Clolar);cytarabine (Cytosar-U); decitabine (Dacogen); cytarabine liposomal(DepoCyt); hydroxyurea (Droxia); pralatrexate (Folotyn); floxuridine(FUDR); gemcitabine (Gemzar); cladribine (Leustatin); fludarabine(Oforta); methotrexate (MTX; Rheumatrex); methotrexate (Trexall);thioguanine (Tabloid); TS-1 or cytarabine (Tarabine PFS).

Exemplary detoxifying agents include, but are not limited to, amifostine(Ethyol) or mesna (Mesnex).

Exemplary interferons include, but are not limited to, interferonalfa-2b (Intron A) or interferon alfa-2a (Roferon-A).

Exemplary polyclonal or monoclonal antibodies include, but are notlimited to, trastuzumab (Herceptin); ofatumumab (Arzerra); bevacizumab(Avastin); rituximab (Rituxan); cetuximab (Erbitux); panitumumab(Vectibix); tositumomab/iodine¹³¹ tositumomab (Bexxar); alemtuzumab(Campath); ibritumomab (Zevalin; In-111; Y-90 Zevalin); gemtuzumab(Mylotarg); eculizumab (Soliris) ordenosumab; nivolumab (Opdivo);pembrolizumab (Keytruda); ipilimumab (Yervoy); pidilizumab;atezolizumab.

Exemplary EGFR inhibitors include, but are not limited to, gefitinib(Iressa); lapatinib (Tykerb); cetuximab (Erbitux); erlotinib (Tarceva);panitumumab (Vectibix); PKI-166; canertinib (CI-1033); matuzumab(Emd7200) or EKB-569.

Exemplary HER2 inhibitors include, but are not limited to, trastuzumab(Herceptin); lapatinib (Tykerb) or AC-480.

Histone Deacetylase Inhibitors include, but are not limited to,vorinostat (Zolinza).

Exemplary hormones include, but are not limited to, tamoxifen (Soltamox;Nolvadex); raloxifene (Evista); megestrol (Megace); leuprolide (Lupron;Lupron Depot; Eligard; Viadur); fulvestrant (Faslodex); letrozole(Femara); triptorelin (Trelstar LA; Trelstar Depot); exemestane(Aromasin); goserelin (Zoladex); bicalutamide (Casodex); anastrozole(Arimidex); fluoxymesterone (Androxy; Halotestin); medroxyprogesterone(Provera; Depo-Provera); estramustine (Emcyt); flutamide (Eulexin);toremifene (Fareston); degarelix (Firmagon); nilutamide (Nilandron);abarelix (Plenaxis); or testolactone (Teslac).

Exemplary mitotic inhibitors include, but are not limited to, paclitaxel(Taxol; Onxol; Abraxane); docetaxel (Taxotere); vincristine (Oncovin;Vincasar PFS); vinblastine (Velban); etoposide (Toposar; Etopophos;VePesid); teniposide (Vumon); ixabepilone (Ixempra); nocodazole;epothilone; vinorelbine (Navelbine); camptothecin (CPT); irinotecan(Camptosar); topotecan (Hycamtin); amsacrine or lamellarin D (LAM-D).

Exemplary MTOR inhibitors include, but are not limited to, everolimus(Afinitor) or temsirolimus (Torisel); rapamune, ridaforolimus; orAP23573.

Exemplary multi-kinase inhibitors include, but are not limited to,sorafenib (Nexavar); sunitinib (Sutent); BIBW 2992; E7080; Zd6474;PKC-412; motesanib; or AP24534.

Exemplary serine/threonine kinase inhibitors include, but are notlimited to, ruboxistaurin; eril/easudil hydrochloride; flavopiridol;seliciclib (CYC202; Roscovitrine); SNS-032 (BMS-387032); Pkc412;bryostatin; KAI-9803;SF1126; VX-680; Azd1152; Arry-142886 (AZD-6244);SCIO-469; GW681323; CC-401; CEP-1347 or PD 332991.

Exemplary tyrosine kinase inhibitors include, but are not limited to,erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib(Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab(Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux);panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath);gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient);dasatinib (Sprycel); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584);CEP-701; SU5614; MLN518; XL999; VX-322; Azd0530; BMS-354825; SKI-606CP-690; AG-490; WHI-P154; WHI-P131; AC-220; or AMG888.

Exemplary VEGF/VEGFR inhibitors include, but are not limited to,bevacizumab (Avastin); sorafenib (Nexavar); sunitinib (Sutent);ranibizumab; pegaptanib; or vandetinib.

Exemplary microtubule targeting drugs include, but are not limited to,paclitaxel, docetaxel, vincristin, vinblastin, nocodazole, epothilonesand navelbine.

Exemplary topoisomerase poison drugs include, but are not limited to,teniposide, etoposide, adriamycin, camptothecin, daunorubicin,dactinomycin, mitoxantrone, amsacrine, epirubicin and idarubicin.

Exemplary taxanes or taxane derivatives include, but are not limited to,paclitaxel and docetaxol.

Exemplary general chemotherapeutic, anti-neoplastic, anti-proliferativeagents include, but are not limited to, altretamine (Hexalen);isotretinoin (Accutane; Amnesteem; Claravis; Sotret); tretinoin(Vesanoid); azacitidine (Vidaza); bortezomib (Velcade) asparaginase(Elspar); levamisole (Ergamisol); mitotane (Lysodren); procarbazine(Matulane); pegaspargase (Oncaspar); denileukin diftitox (Ontak);porfimer (Photofrin); aldesleukin (Proleukin); lenalidomide (Revlimid);bexarotene (Targretin); thalidomide (Thalomid); temsirolimus (Torisel);arsenic trioxide (Trisenox); verteporfin (Visudyne); mimosine(Leucenol); (1M tegafur—0.4 M 5-chloro-2,4-dihydroxypyrimidine—1 Mpotassium oxonate) or lovastatin.

In another aspect, the additional chemotherapeutic agent can be acytokine such as G-CSF (granulocyte colony stimulating factor). Inanother aspect, a compound of the present disclosure, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, may be administered in combination with radiationtherapy. Radiation therapy can also be administered in combination witha compound of the present disclosure and another chemotherapeutic agentdescribed herein as part of a multiple agent therapy. In yet anotheraspect, a compound of the present disclosure, or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof, maybe administered in combination with standard chemotherapy combinationssuch as, but not restricted to, CMF (cyclophosphamide, methotrexate and5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil),AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin,and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, andpaclitaxel), rituximab, Xeloda (capecitabine), Cisplatin (CDDP),Carboplatin, TS-1 (tegafur, gimestat and otastat potassium at a molarratio of 1:0.4:1), Camptothecin-11 (CPT-11, Irinotecan or CamptosarTM)or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).

In certain aspects, a compound of the present disclosure, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, may be administered with an inhibitor of an enzyme,such as a receptor or non-receptor kinase. Receptor and non-receptorkinases of the disclosure are, for example, tyrosine kinases orserine/threonine kinases. Kinase inhibitors of the disclosure are smallmolecules, polynucleic acids, polypeptides, or antibodies.

Exemplary kinase inhibitors include, but are not limited to, BIBW 2992(targets EGFR and Erb2), Cetuximab/Erbitux (targets Erb1),Imatinib/Gleevic (targets Bcr-Abl), Trastuzumab (targets Erb2),Gefitinib/Iressa (targets EGFR), Ranibizumab (targets VEGF), Pegaptanib(targets VEGF), Erlotinib/Tarceva (targets Erb1), Nilotinib (targetsBcr-Abl), Lapatinib (targets Erb1 and Erb2/Her2), GW-572016/lapatinibditosylate (targets HER2/Erb2), Panitumumab/Vectibix (targets EGFR),Vandetinib (targets RET/VEGFR), E7080 (multiple targets including RETand VEGFR), Herceptin (targets HER2/Erb2), PKI-166 (targets EGFR),Canertinib/CI-1033 (targets EGFR), Sunitinib/SU-11464/Sutent (targetsEGFR and FLT3), Matuzumab/Emd7200 (targets EGFR), EKB-569 (targetsEGFR), Zd6474 (targets EGFR and VEGFR), PKC-412 (targets VEGR and FLT3),Vatalanib/Ptk787/ZK222584 (targets VEGR), CEP-701 (targets FLT3), SU5614(targets FLT3), MLN518 (targets FLT3), XL999 (targets FLT3), VX-322(targets FLT3), Azd0530 (targets SRC), BMS-354825 (targets SRC), SKI-606(targets SRC), CP-690 (targets JAK), AG-490 (targets JAK), WHI-P154(targets JAK), WHI-P131 (targets JAK), sorafenib/Nexavar (targets RAFkinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, KIT, FLT-3, and RET),Dasatinib/Sprycel (BCR/ABL and Src), AC-220 (targets Flt3), AC-480(targets all HER proteins, “panHER”), Motesanib diphosphate (targetsVEGF1-3, PDGFR, and c-kit), Denosumab (targets RANKL, inhibits SRC),AMG888 (targets HERS), and AP24534 (multiple targets including Flt3).

Exemplary serine/threonine kinase inhibitors include, but are notlimited to, Rapamune (targets mTOR/FRAP1), Deforolimus (targets mTOR),Certican/Everolimus (targets mTOR/FRAP1), AP23573 (targets mTOR/FRAP1),Eril/Fasudil hydrochloride (targets RHO), Flavopiridol (targets CDK),Seliciclib/CYC202/Roscovitrine (targets CDK), SNS-032/BMS-387032(targets CDK), Ruboxistaurin (targets PKC), Pkc412 (targets PKC),Bryostatin (targets PKC), KAI-9803 (targets PKC), SF1126 (targets PI3K),VX-680 (targets Aurora kinase), Azd1152 (targets Aurora kinase),Arry-142886/AZD-6244 (targets MAP/MEK), SCIO-469 (targets MAP/MEK),GW681323 (targets MAP/MEK), CC-401 (targets JNK), CEP-1347 (targetsJNK), and PD 332991 (targets CDK).

Contemplated second active agents also include those administered totreat type 2 diabetes such as sulfonylureas (e.g., chlorpropamide,glipizide, glyburide, glimepiride); meglitinides (e.g., repaglinide andnateglinide); biguanides (e.g., metformin); thiazolidinediones(rosiglitazone, troglitazone, and pioglitazone); glucagon-like 1 peptidemimetics (e.g. exenatide and liraglutide); sodium-glucose cotransporterinhibitors (e.g., dapagliflozin), dipeptidyl peptidase 4 inhibitors(e.g. gliptins), sodium—glucose linked transporter inhibitors, renininhibitors, and alpha-glucosidase inhibitors (e.g., acarbose andmeglitol), and/or those administered to treat cardiac disorders andconditions, such as hypertension, dyslipidemia, ischemic heart disease,cardiomyopathy, cardiac infarction, stroke, venous thromboembolicdisease and pulmonary hypertension, which have been linked to overweightor obesity, for example, chlorthalidone; hydrochlorothiazide;indapamide, metolazone; loop diuretics (e.g., bumetanide, ethacrynicacid, furosemide, lasix, torsemide); potassium-sparing agents (e.g.,amiloride hydrochloride, spironolactone, and triamterene); peripheralagents (e.g., reserpine); central alpha-agonists (e.g., clonidinehydrochloride, guanabenz acetate, guanfacine hydrochloride, andmethyldopa); alpha-blockers (e.g., doxazosin mesylate, prazosinhydrochloride, and terazosin hydrochloride); beta-blockers (e.g.,acebutolol, atenolol, betaxolol, nisoprolol fumarate, carteololhydrochloride, metoprolol tartrate, metoprolol succinate, Nadolol,penbutolol sulfate, pindolol, propranolol hydrochloride, and timololmaleate); combined alpha- and beta-blockers (e.g., carvedilol andlabetalol hydrochloride); direct vasodilators (e.g., hydralazinehydrochloride and minoxidil); calcium antagonists (e.g., diltiazemhydrochloride and verapamil hydrochloride); dihydropyridines (e.g.,amlodipine besylate, felodipine, isradipine, nicardipine, nifedipine,and nisoldipine); ACE inhibitors (benazepril hydrochloride, captopril,enalapril maleate, fosinopril sodium, lisinopril, moexipril, quinaprilhydrochloride, ramipril, trandolapril); angiotensin II receptor blockers(e.g., losartan potassium, valsartan, and Irbesartan); and combinationsthereof, as well as statins such as mevastatin, lovastatin, pravastatin,simvastatin, velostatin, dihydrocompactin, fluvastatin, atorvastatin,dalvastatin, carvastatin, crilvastatin, bevastatin, cefvastatin,rosuvastatin, pitavastatin, and glenvastatin., typically for treatmentof dyslipidemia.

Other second active agents that may be co-administered (e.g.sequentially or simultaneously) include agents administered to treatischemic heart disease including statins, nitrates (e.g., IsosorbideDinitrate and Isosorbide Mononitrate), beta-blockers, and calciumchannel antagonists, agents administered to treat cardiomyopathyincluding inotropic agents (e.g., Digoxin), diuretics (e.g.,Furosemide), ACE inhibitors, calcium antagonists, anti-arrhythmic agents(e.g., Sotolol, Amiodarone and Disopyramide), and beta-blockers, agentsadministered to treat cardiac infarction including ACE inhibitors,Angiotensin II receptor blockers, direct vasodilators, beta blockers,anti-arrhythmic agents and thrombolytic agents (e.g., Alteplase,Retaplase, Tenecteplase, Anistreplase, and Urokinase), agentsadministered to treat strokes including anti-platelet agents (e.g.,Aspirin, Clopidogrel, Dipyridamole, and Ticlopidine), anticoagulantagents (e.g., Heparin), and thrombolytic agents, agents administered totreat venous thromboembolic disease including anti-platelet agents,anticoagulant agents, and thrombolytic agents, agents administered totreat pulmonary hypertension include inotropic agents, anticoagulantagents, diuretics, potassium (e.g., K-dur), vasodilators (e.g.,Nifedipine and Diltiazem), Bosentan, Epoprostenol, and Sildenafil,agents administered to treat asthma include bronchodilators,anti-inflammatory agents, leukotriene blockers, and anti-Ige agents.Particular asthma agents include Zafirlukast, Flunisolide,Triamcinolone, Beclomethasone, Terbutaline, Fluticasone, Formoterol,Beclomethasone, Salmeterol, Theophylline, and Xopenex, agentsadministered to treat sleep apnea include Modafinil and amphetamines,agents administered to treat nonalcoholic fatty liver disease includeantioxidants (e.g., Vitamins E and C), insulin sensitizers (Metformin,Pioglitazone, Rosiglitazone, and Betaine), hepatoprotectants, andlipid-lowering agents, agents administered to treat osteoarthritis ofweight-bearing joints include Acetaminophen, non-steroidalanti-inflammatory agents (e.g., Ibuprofen, Etodolac, Oxaprozin,Naproxen, Diclofenac, and Nabumetone), COX-2 inhibitors (e.g.,Celecoxib), steroids, supplements (e.g. glucosamine and chondroitinsulfate), and artificial joint fluid, agents administered to treatPrader-Willi Syndrome include human growth hormone (HGH), somatropin,and weight loss agents (e.g., Orlistat, Sibutramine, Methamphetamine,Ionamin, Phentermine, Bupropion, Diethylpropion, Phendimetrazine,Benzphetermine, and Topamax), agents administered to treat polycysticovary syndrome include insulin-sensitizers, combinations of syntheticestrogen and progesterone, Spironolactone, Eflornithine, and Clomiphene,agents administered to treat erectile dysfunction includephosphodiesterase inhibitors (e.g., Tadalafil, Sildenafil citrate, andVardenafil), prostaglandin E analogs (e.g., Alprostadil), alkaloids(e.g., Yohimbine), and testosterone, agents administered to treatinfertility include Clomiphene, Clomiphene citrate, Bromocriptine,Gonadotropin-releasing Hormone (GnRH), GnRH agonist, GnRH antagonist,Tamoxifen/nolvadex, gonadotropins, Human Chorionic Gonadotropin (HCG),Human Menopausal Gonadotropin (HmG), progesterone, recombinant folliclestimulating hormone (FSH), Urofollitropin, Heparin, Follitropin alfa,and Follitropin beta, agents administered to treat obstetriccomplications include Bupivacaine hydrochloride, Dinoprostone PGE2,Meperidine HCl, Ferro-folic-500/iberet-folic-500, Meperidine,Methylergonovine maleate, Ropivacaine HCl, Nalbuphine HCl, OxymorphoneHCl, Oxytocin, Dinoprostone, Ritodrine, Scopolamine hydrobromide,Sufentanil citrate, and Oxytocic, agents administered to treatdepression include serotonin reuptake inhibitors (e.g., Fluoxetine,Escitalopram, Citalopram, Paroxetine, Sertraline, and Venlafaxine);tricyclic antidepressants (e.g., Amitriptyline, Amoxapine, Clomipramine,Desipramine, Dosulepin hydrochloride, Doxepin, Imipramine, Iprindole,Lofepramine, Nortriptyline, Opipramol, Protriptyline, and Trimipramine);monoamine oxidase inhibitors (e.g., Isocarboxazid, Moclobemide,Phenelzine, Tranylcypromine, Selegiline, Rasagiline, Nialamide,Iproniazid, Iproclozide, Toloxatone, Linezolid, Dienolide kavapyronedesmethoxyyangonin, and Dextroamphetamine); psychostimulants (e.g.,Amphetamine, Methamphetamine, Methylphenidate, and Arecoline);antipsychotics (e.g., Butyrophenones, Phenothiazines, Thioxanthenes,Clozapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone,Amisulpride, Paliperidone, Symbyax, Tetrabenazine, and Cannabidiol); andmood stabilizers (e.g., Lithium carbonate, Valproic acid, Divalproexsodium, Sodium valproate, Lamotrigine, Carbamazepine, Gabapentin,Oxcarbazepine, and Topiramate), agents administered to treat anxietyinclude serotonin reuptake inhibitors, mood stabilizers, benzodiazepines(e.g., Alprazolam, Clonazepam, Diazepam, and Lorazepam), tricyclicantidepressants, monoamine oxidase inhibitors, and beta-blockers, andother weight loss agents, including serotonin and noradrenergicre-uptake inhibitors; noradrenergic re-uptake inhibitors; selectiveserotonin re-uptake inhibitors; and intestinal lipase inhibitors.Particular weight loss agents include orlistat, sibutramine,methamphetamine, ionamin, phentermine, bupropion, diethylpropion,phendimetrazine, benzphetermine, and topamax.

As used herein, “treating” or “treat” describes the management and careof a patient for the purpose of combating a disease, condition, ordisorder and includes the administration of a compound of the presentdisclosure, or a pharmaceutically acceptable salt, prodrug, metabolite,polymorph or solvate thereof, to alleviate the symptoms or complicationsof a disease, condition or disorder, or to eliminate the disease,condition or disorder.

A compound of the present disclosure, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, can also beused to prevent a disease, condition or disorder. As used herein,“preventing” or “prevent” describes reducing or eliminating the onset ofthe symptoms or complications of the disease, condition or disorder.

As used herein, the terms “ameliorate” or “alleviate” are meant todescribe a process by which the severity of a sign or symptom of adisorder is decreased. Importantly, a sign or symptom can be alleviatedwithout being eliminated. In a preferred aspect, the administration ofpharmaceutical compositions of the disclosure leads to the eliminationof a sign or symptom, however, elimination is not required. Effectivedosages are expected to decrease the severity of a sign or symptom. Forinstance, a sign or symptom of a disorder such as cancer, which canoccur in multiple locations, is alleviated if the severity of the canceris decreased within at least one of multiple locations.

As used herein, the term “severity” is meant to describe the potentialof cancer to transform from a precancerous, or benign, state into amalignant state. Alternatively, or in addition, severity is meant todescribe a cancer stage, for example, according to the TNM system(accepted by the International Union Against Cancer (UICC) and theAmerican Joint Committee on Cancer (AJCC)) or by other art-recognizedmethods. Cancer stage refers to the extent or severity of the cancer,based on factors such as the location of the primary tumor, tumor size,number of tumors, and lymph node involvement (spread of cancer intolymph nodes). Alternatively, or in addition, severity is meant todescribe the tumor grade by art-recognized methods (see, National CancerInstitute). Tumor grade is a system used to classify cancer cells interms of how abnormal they look under a microscope and how quickly thetumor is likely to grow and spread. Many factors are considered whendetermining tumor grade, including the structure and growth pattern ofthe cells. The specific factors used to determine tumor grade vary witheach type of cancer. Severity also describes a histologic grade, alsocalled differentiation, which refers to how much the tumor cellsresemble normal cells of the same tissue type (see, National CancerInstitute). Furthermore, severity describes a nuclear grade, whichrefers to the size and shape of the nucleus in tumor cells and thepercentage of tumor cells that are dividing (see, National CancerInstitute).

In another aspect of the disclosure, severity describes the degree towhich a tumor has secreted growth factors, degraded the extracellularmatrix, become vascularized, lost adhesion to juxtaposed tissues, ormetastasized. Moreover, severity describes the number of locations towhich a primary tumor has metastasized. Finally, severity includes thedifficulty of treating tumors of varying types and locations. Forexample, inoperable tumors, those cancers which have greater access tomultiple body systems (hematological and immunological tumors), andthose which are the most resistant to traditional treatments areconsidered most severe. In these situations, prolonging the lifeexpectancy of the subject and/or reducing pain, decreasing theproportion of cancerous cells or restricting cells to one system, andimproving cancer stage/tumor grade/histological grade/nuclear grade areconsidered alleviating a sign or symptom of the cancer.

As used herein the term “symptom” is defined as an indication ofdisease, illness, injury, or that something is not right in the body.Symptoms are felt or noticed by the individual experiencing the symptom,but may not easily be noticed by others. Others are defined asnon-health-care professionals.

As used herein the term “sign” is also defined as an indication thatsomething is not right in the body. But signs are defined as things thatcan be seen by a doctor, nurse, or other health care professional.

Cancer is a group of diseases that may cause almost any sign or symptom.The signs and symptoms will depend on where the cancer is, the size ofthe cancer, and how much it affects the nearby organs or structures. Ifa cancer spreads (metastasizes), then symptoms may appear in differentparts of the body.

As a cancer grows, it begins to push on nearby organs, blood vessels,and nerves. This pressure creates some of the signs and symptoms ofcancer. If the cancer is in a critical area, such as certain parts ofthe brain, even the smallest tumor can cause early symptoms.

But sometimes cancers start in places where it does not cause anysymptoms until the cancer has grown quite large. Pancreas cancers, forexample, do not usually grow large enough to be felt from the outside ofthe body. Some pancreatic cancers do not cause symptoms until they beginto grow around nearby nerves (this causes a backache). Others growaround the bile duct, which blocks the flow of bile and leads to ayellowing of the skin known as jaundice. By the time a pancreatic cancercauses these signs or symptoms, it has usually reached an advancedstage.

A cancer may also cause symptoms such as fever, fatigue, or weight loss.This may be because cancer cells use up much of the body's energy supplyor release substances that change the body's metabolism. Or the cancermay cause the immune system to react in ways that produce thesesymptoms.

Sometimes, cancer cells release substances into the bloodstream thatcause symptoms not usually thought to result from cancers. For example,some cancers of the pancreas can release substances which cause bloodclots to develop in veins of the legs. Some lung cancers makehormone-like substances that affect blood calcium levels, affectingnerves and muscles and causing weakness and dizziness.

Cancer presents several general signs or symptoms that occur when avariety of subtypes of cancer cells are present. Most people with cancerwill lose weight at some time with their disease. An unexplained(unintentional) weight loss of 10 pounds or more may be the first signof cancer, particularly cancers of the pancreas, stomach, esophagus, orlung.

Fever is very common with cancer, but is more often seen in advanceddisease. Almost all patients with cancer will have fever at some time,especially if the cancer or its treatment affects the immune system andmakes it harder for the body to fight infection. Less often, fever maybe an early sign of cancer, such as with leukemia or lymphoma.

Fatigue may be an important symptom as cancer progresses. It may happenearly, though, in cancers such as with leukemia, or if the cancer iscausing an ongoing loss of blood, as in some colon or stomach cancers.

Pain may be an early symptom with some cancers such as bone cancers ortesticular cancer. But most often pain is a symptom of advanced disease.

Along with cancers of the skin, some internal cancers can cause skinsigns that can be seen. These changes include the skin looking darker(hyperpigmentation), yellow (jaundice), or red (erythema); itching; orexcessive hair growth.

Alternatively, or in addition, cancer subtypes present specific signs orsymptoms. Changes in bowel habits or bladder function could indicatecancer. Long-term constipation, diarrhea, or a change in the size of thestool may be a sign of colon cancer. Pain with urination, blood in theurine, or a change in bladder function (such as more frequent or lessfrequent urination) could be related to bladder or prostate cancer.

Changes in skin condition or appearance of a new skin condition couldindicate cancer. Skin cancers may bleed and look like sores that do notheal. A long-lasting sore in the mouth could be an oral cancer,especially in patients who smoke, chew tobacco, or frequently drinkalcohol. Sores on the penis or vagina may either be signs of infectionor an early cancer.

Unusual bleeding or discharge could indicate cancer. Unusual bleedingcan happen in either early or advanced cancer. Blood in the sputum(phlegm) may be a sign of lung cancer. Blood in the stool (or a dark orblack stool) could be a sign of colon or rectal cancer. Cancer of thecervix or the endometrium (lining of the uterus) can cause vaginalbleeding. Blood in the urine may be a sign of bladder or kidney cancer.A bloody discharge from the nipple may be a sign of breast cancer.

A thickening or lump in the breast or in other parts of the body couldindicate the presence of a cancer. Many cancers can be felt through theskin, mostly in the breast, testicle, lymph nodes (glands), and the softtissues of the body. A lump or thickening may be an early or late signof cancer. Any lump or thickening could be indicative of cancer,especially if the formation is new or has grown in size.

Indigestion or trouble swallowing could indicate cancer. While thesesymptoms commonly have other causes, indigestion or swallowing problemsmay be a sign of cancer of the esophagus, stomach, or pharynx (throat).

Recent changes in a wart or mole could be indicative of cancer. Anywart, mole, or freckle that changes in color, size, or shape, or losesits definite borders indicates the potential development of cancer. Forexample, the skin lesion may be a melanoma.

A persistent cough or hoarseness could be indicative of cancer. A coughthat does not go away may be a sign of lung cancer. Hoarseness can be asign of cancer of the larynx (voice box) or thyroid.

While the signs and symptoms listed above are the more common ones seenwith cancer, there are many others that are less common and are notlisted here. However, all art-recognized signs and symptoms of cancerare contemplated and encompassed by the instant disclosure.

Treating cancer can result in a reduction in size of a tumor. Areduction in size of a tumor may also be referred to as “tumorregression”. Preferably, after treatment, tumor size is reduced by 5% orgreater relative to its size prior to treatment; more preferably, tumorsize is reduced by 10% or greater; more preferably, reduced by 20% orgreater; more preferably, reduced by 30% or greater; more preferably,reduced by 40% or greater; even more preferably, reduced by 50% orgreater; and most preferably, reduced by greater than 75% or greater.Size of a tumor may be measured by any reproducible means ofmeasurement. The size of a tumor may be measured as a diameter of thetumor.

Treating cancer can result in a reduction in tumor volume. Preferably,after treatment, tumor volume is reduced by 5% or greater relative toits size prior to treatment; more preferably, tumor volume is reduced by10% or greater; more preferably, reduced by 20% or greater; morepreferably, reduced by 30% or greater; more preferably, reduced by 40%or greater; even more preferably, reduced by 50% or greater; and mostpreferably, reduced by greater than 75% or greater. Tumor volume may bemeasured by any reproducible means of measurement.

Treating cancer results in a decrease in number of tumors. Preferably,after treatment, tumor number is reduced by 5% or greater relative tonumber prior to treatment; more preferably, tumor number is reduced by10% or greater; more preferably, reduced by 20% or greater; morepreferably, reduced by 30% or greater; more preferably, reduced by 40%or greater; even more preferably, reduced by 50% or greater; and mostpreferably, reduced by greater than 75%. Number of tumors may bemeasured by any reproducible means of measurement. The number of tumorsmay be measured by counting tumors visible to the naked eye or at aspecified magnification. Preferably, the specified magnification is 2×,3×, 4×, 5×, 10×, or 50×.

Treating cancer can result in a decrease in number of metastatic lesionsin other tissues or organs distant from the primary tumor site.Preferably, after treatment, the number of metastatic lesions is reducedby 5% or greater relative to number prior to treatment; more preferably,the number of metastatic lesions is reduced by 10% or greater; morepreferably, reduced by 20% or greater; more preferably, reduced by 30%or greater; more preferably, reduced by 40% or greater; even morepreferably, reduced by 50% or greater; and most preferably, reduced bygreater than 75%. The number of metastatic lesions may be measured byany reproducible means of measurement. The number of metastatic lesionsmay be measured by counting metastatic lesions visible to the naked eyeor at a specified magnification. Preferably, the specified magnificationis 2×, 3×, 4×, 5×, 10×, or 50×.

Treating cancer can result in an increase in average survival time of apopulation of treated subjects in comparison to a population receivingcarrier alone. Preferably, the average survival time is increased bymore than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in an increase in average survival time of apopulation of treated subjects in comparison to a population ofuntreated subjects. Preferably, the average survival time is increasedby more than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in increase in average survival time of apopulation of treated subjects in comparison to a population receivingmonotherapy with a drug that is not a compound of the presentdisclosure, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof. Preferably, the average survival time isincreased by more than 30 days; more preferably, by more than 60 days;more preferably, by more than 90 days; and most preferably, by more than120 days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in a decrease in the mortality rate of apopulation of treated subjects in comparison to a population receivingcarrier alone. Treating cancer can result in a decrease in the mortalityrate of a population of treated subjects in comparison to an untreatedpopulation. Treating cancer can result in a decrease in the mortalityrate of a population of treated subjects in comparison to a populationreceiving monotherapy with a drug that is not a compound of the presentdisclosure, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof Preferably, the mortality rate is decreasedby more than 2%; more preferably, by more than 5%; more preferably, bymore than 10%; and most preferably, by more than 25%. A decrease in themortality rate of a population of treated subjects may be measured byany reproducible means. A decrease in the mortality rate of a populationmay be measured, for example, by calculating for a population theaverage number of disease-related deaths per unit time followinginitiation of treatment with an active compound. A decrease in themortality rate of a population may also be measured, for example, bycalculating for a population the average number of disease-relateddeaths per unit time following completion of a first round of treatmentwith an active compound.

Treating cancer can result in a decrease in tumor growth rate.Preferably, after treatment, tumor growth rate is reduced by at least 5%relative to number prior to treatment; more preferably, tumor growthrate is reduced by at least 10%; more preferably, reduced by at least20%; more preferably, reduced by at least 30%; more preferably, reducedby at least 40%; more preferably, reduced by at least 50%; even morepreferably, reduced by at least 50%; and most preferably, reduced by atleast 75%. Tumor growth rate may be measured by any reproducible meansof measurement. Tumor growth rate can be measured according to a changein tumor diameter per unit time.

Treating cancer can result in a decrease in tumor regrowth. Preferably,after treatment, tumor regrowth is less than 5%; more preferably, tumorregrowth is less than 10%; more preferably, less than 20%; morepreferably, less than 30%; more preferably, less than 40%; morepreferably, less than 50%; even more preferably, less than 50%; and mostpreferably, less than 75%. Tumor regrowth may be measured by anyreproducible means of measurement. Tumor regrowth is measured, forexample, by measuring an increase in the diameter of a tumor after aprior tumor shrinkage that followed treatment. A decrease in tumorregrowth is indicated by failure of tumors to reoccur after treatmenthas stopped.

Treating or preventing a cell proliferative disorder can result in areduction in the rate of cellular proliferation. Preferably, aftertreatment, the rate of cellular proliferation is reduced by at least 5%;more preferably, by at least 10%; more preferably, by at least 20%; morepreferably, by at least 30%; more preferably, by at least 40%; morepreferably, by at least 50%; even more preferably, by at least 50%; andmost preferably, by at least 75%. The rate of cellular proliferation maybe measured by any reproducible means of measurement. The rate ofcellular proliferation is measured, for example, by measuring the numberof dividing cells in a tissue sample per unit time.

Treating or preventing a cell proliferative disorder can result in areduction in the proportion of proliferating cells. Preferably, aftertreatment, the proportion of proliferating cells is reduced by at least5%; more preferably, by at least 10%; more preferably, by at least 20%;more preferably, by at least 30%; more preferably, by at least 40%; morepreferably, by at least 50%; even more preferably, by at least 50%; andmost preferably, by at least 75%. The proportion of proliferating cellsmay be measured by any reproducible means of measurement. Preferably,the proportion of proliferating cells is measured, for example, byquantifying the number of dividing cells relative to the number ofnondividing cells in a tissue sample. The proportion of proliferatingcells can be equivalent to the mitotic index.

Treating or preventing a cell proliferative disorder can result in adecrease in size of an area or zone of cellular proliferation.Preferably, after treatment, size of an area or zone of cellularproliferation is reduced by at least 5% relative to its size prior totreatment; more preferably, reduced by at least 10%; more preferably,reduced by at least 20%; more preferably, reduced by at least 30%; morepreferably, reduced by at least 40%; more preferably, reduced by atleast 50%; even more preferably, reduced by at least 50%; and mostpreferably, reduced by at least 75%. Size of an area or zone of cellularproliferation may be measured by any reproducible means of measurement.The size of an area or zone of cellular proliferation may be measured asa diameter or width of an area or zone of cellular proliferation.

Treating or preventing a cell proliferative disorder can result in adecrease in the number or proportion of cells having an abnormalappearance or morphology. Preferably, after treatment, the number ofcells having an abnormal morphology is reduced by at least 5% relativeto its size prior to treatment; more preferably, reduced by at least10%; more preferably, reduced by at least 20%; more preferably, reducedby at least 30%; more preferably, reduced by at least 40%; morepreferably, reduced by at least 50%; even more preferably, reduced by atleast 50%; and most preferably, reduced by at least 75%. An abnormalcellular appearance or morphology may be measured by any reproduciblemeans of measurement. An abnormal cellular morphology can be measured bymicroscopy, e.g., using an inverted tissue culture microscope. Anabnormal cellular morphology can take the form of nuclear pleiomorphism.

Treating cancer or a cell proliferative disorder can result in celldeath, and preferably, cell death results in a decrease of at least 10%in number of cells in a population. More preferably, cell death means adecrease of at least 20%; more preferably, a decrease of at least 30%;more preferably, a decrease of at least 40%; more preferably, a decreaseof at least 50%; most preferably, a decrease of at least 75%. Number ofcells in a population may be measured by any reproducible means. Anumber of cells in a population can be measured by fluorescenceactivated cell sorting (FACS), immunofluorescence microscopy and lightmicroscopy. Methods of measuring cell death are as shown in Li et al.,Proc Natl Acad Sci USA. 100(5): 2674-8, 2003. In an aspect, cell deathoccurs by apoptosis.

Preferably, an effective amount of a compound of the present disclosure,or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, is not significantly cytotoxic to normal cells. Atherapeutically effective amount of a compound is not significantlycytotoxic to normal cells if administration of the compound in atherapeutically effective amount does not induce cell death in greaterthan 10% of normal cells. A therapeutically effective amount of acompound does not significantly affect the viability of normal cells ifadministration of the compound in a therapeutically effective amountdoes not induce cell death in greater than 10% of normal cells. In anaspect, cell death occurs by apoptosis.

Contacting a cell with a compound of the present disclosure, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, can induce or activate cell death selectively in cancercells. Administering to a subject in need thereof a compound of thepresent disclosure, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, can induce or activate celldeath selectively in cancer cells. Contacting a cell with a compound ofthe present disclosure, or a pharmaceutically acceptable salt, prodrug,metabolite, polymorph or solvate thereof, can induce cell deathselectively in one or more cells affected by a cell proliferativedisorder. Preferably, administering to a subject in need thereof acompound of the present disclosure, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, induces celldeath selectively in one or more cells affected by a cell proliferativedisorder.

The present disclosure relates to a method of treating or preventingcancer by administering a compound of the present disclosure, or apharmaceutically acceptable salt, prodrug, metabolite, polymorph orsolvate thereof, to a subject in need thereof, where administration ofthe compound of the present disclosure, or a pharmaceutically acceptablesalt, prodrug, metabolite, polymorph or solvate thereof, results in oneor more of the following: accumulation of cells in G1 and/or S phase ofthe cell cycle, cytotoxicity via cell death in cancer cells without asignificant amount of cell death in normal cells, antitumor activity inanimals with a therapeutic index of at least 2, and activation of a cellcycle checkpoint. As used herein, “therapeutic index” is the maximumtolerated dose divided by the efficacious dose.

A “therapeutically effective amount” of a compound, with respect to usein treatment, refers to an amount of a compound in a preparation which,when administered as part of a desired dosage regimen (to a mammal,preferably a human) alleviates a symptom, ameliorates a condition, orslows or prevents the onset of disease conditions according toclinically acceptable standards for the disorder or condition to betreated or the cosmetic purpose, e.g., at a reasonable benefit/riskratio applicable to any medical treatment. A “therapeutically effectiveamount” is synonymous with “efficacious dose”.

As used herein, an “effective dosage” or “effective amount” of drug,compound, or pharmaceutical composition is an amount sufficient toeffect beneficial or desired results. For prophylactic use, beneficialor desired results include results such as eliminating or reducing therisk, lessening the severity, or delaying the outset of the disease,including biochemical, histological and/or behavioral symptoms of thedisease, its complications and intermediate pathological phenotypespresenting during development of the disease. For therapeutic use,beneficial or desired results include clinical results such as reducingintensity, duration, or frequency of attack of the disease, anddecreasing one or more symptoms resulting from the disease (biochemical,histological and/or behavioral), including its complications andintermediate pathological phenotypes presenting during development ofthe disease, increasing the quality of life of those suffering from thedisease, decreasing the dose of other medications required to treat thedisease, enhancing effect of another medication, and/or delaying theprogression of the disease of patients. An effective dosage can beadministered in one or more administrations. For purposes of thisdisclosure, an effective dosage of drug, compound, or pharmaceuticalcomposition is an amount sufficient to accomplish prophylactic ortherapeutic treatment either directly or indirectly. As is understood inthe clinical context, an effective dosage of a drug, compound, orpharmaceutical composition may or may not be achieved in conjunctionwith another drug, compound, or pharmaceutical composition. Thus, an“effective dosage” may be considered in the context of administering oneor more therapeutic agents, and a single agent may be considered to begiven in an effective amount if, in conjunction with one or more otheragents, a desirable result may be or is achieved. For example, aneffective amount of a compound of the present disclosure for treating aproliferation disorder is an amount sufficient to treat or ameliorateone or more symptoms associated with the proliferation disorder. An“effective amount” is an amount sufficient to result in one or more ofthe following (which can also correspond to various aspects of thedisclosure): reducing tumor size, reducing tumor volume, reducing tumornumber, decrease in metastatic lesions, increase in survival time,decrease in mortality rate, decrease in tumor growth rate, decrease intumor regrowth, reduction in proportion of proliferating cells, orincreasing the quality of life of those suffering from a proliferationdisorder.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays, e.g., of neoplastic cells, orin animal models, usually rats, mice, rabbits, dogs, or pigs. The animalmodel may also be used to determine the appropriate concentration rangeand route of administration. Such information can then be used todetermine useful doses and routes for administration in humans.Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred. Thedosage may vary within this range depending upon the dosage formemployed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. In providing asubject with one or more of the compounds described herein, the dosageof administered compound(s) will vary depending upon such factors as thesubject's age, weight, height, sex, general medical condition, previousmedical history, disease progression, route of administration,formulation and the like.

Dosages for a compound of the present disclosure may be determinedempirically in individuals who have been given one or moreadministration(s). Individuals are given incremental dosages of acompound of the present disclosure. To assess efficacy of a compound ofthe present disclosure, markers of the disease state can be monitored.It will be apparent to one of skill in the art that the dosage will varydepending on the individual, the stage of the disease (e.g., tumor size,tumor grade, tumor number), and the past and concurrent treatments beingused.

Toxicity and therapeutic efficacy of compounds of the present disclosurecan be determined by standard pharmaceutical procedures in experimentalanimals. Toxic doses may be determined as the maximum tolerated dose(MTD) or alternatively the LD50 (the dose lethal to 50% of thepopulation). Efficacious doses may be determined as the ED50 (the dosetherapeutically effective in 50% of the population) or dose required toprovide some average amount of change in an animal (e.g. the doserequired to provide an average reduction in systolic blood pressure of10 mm Hg in a group of subjects).

Ideally, the efficacious and toxic doses may be determined in the samespecies. However if they are determined in different species, allometricscaling may be used to translate the efficacious or toxic dose toanother species. The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD50/ED50. Incomparing mice to rats, the commonly accepted scaling factor is 2; therat dose is estimated to be one-half the dose in mice. Thus if the toxicdose in a rat is 100 mg/kg and the efficacious dose in a mouse is 1mg/kg, the therapeutic index in the rat may be calculated as efficaciousdose in rat equals 1 mg/kg/2 or 0.5 mg/kg and the therapeutic index is200. FDA defines a drug as having a narrow therapeutic range if: (a)less than 2-fold difference between median lethal and median effectivedose, or (b) less than 2-fold difference between minimum toxic andminimum effective concentrations in the blood.

Compounds of the present disclosure which exhibit large therapeuticindices are preferred. While compounds of the present disclosure thatexhibit toxic side effects may be used, care should be taken to design adelivery system that targets such compounds of the present disclosure tothe site of affected tissue in order to minimize potential damage touninfected cells and, thereby, reduce side effects.

The data obtained from animal studies can be used in formulating a rangeof dosage for use in humans. The dosage of such compounds of the presentdisclosure lies preferably within a range of circulating concentrationsthat include the efficacious dose range with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For compounds of thepresent disclosure with a MW less than 1000, the therapeuticallyeffective dose can be estimated initially from cell culture assays whileanimal models will provide a better estimation of dose for conjugateswhere the linker requires cleavage to release an active moiety. Suchinformation can be used to more accurately determine useful doses inhumans. It is well known in the art that polymer conjugation dilutes theactivity of the active moiety (polymer is a diluent). This isexemplified in the mouse dosing model of the anti-cancer drugs shown inthe following Table.

Drug Parent Drug Dose (mg/kg) Conjugate Conjugate Dose (mg/kg) TNP-47030 (qod) XMT-1107  800 Docetaxel 12 (Q4d) Opaxio  480 CPT-11 20 (q2d)EZN-2208  145 (q2d) Doxorubicin  5 (q4d) PK1  62 (q7d) Carboplatin 60(Qd) AP-5356 2200

The polymer conjugate and modified compounds of the present disclosuresurprisingly provide superior efficacy and lower toxicity when comparedto the unconjugated and or unmodified parent drug/active moiety.

For example, the fumagillol conjugates and modified fumagillol compoundsof the present disclosure are surprisingly superior to fumagillol smallmolecules as they provide increased tumor reduction in DIO mice atequivalent molar doses. The compounds of the present disclosure may beused at lower molar doses and with less frequent dosing to provideequivalent tumor reduction. Lower molar doses and reduced dosingfrequency reduce systemic drug exposure and systemic drug toxicity.

Traditional polymer conjugates dilute activity, increase doses by 5-20×and provide little change in therapeutic index (<2×). In contrast, thepolymer conjugate compounds of the present disclosure surprisingly andunexpectedly provide an enhanced therapeutic index (order of magnitudeimprovement) and demonstrate increased activity at a reduced dose.

In the methods of the present disclosure, the polymer conjugatecompounds of the present disclosure surprisingly demonstrate efficacywith less frequent dose administration (e.g., q4d, dosing every fourthday, q7d, dosing every seventh day, q8d, dosing every eighth day), doseswhich are decreased at least 84 mole % fumagillol equivalent, reducedAUC in non-target compartments while therapeutic index is increased(>10×).

In another aspect, provided herein are effective dosages of a compoundof the present disclosure. For example, provided here are methods thatinclude administering doses of a compound of the present disclosure thatare effective for tumor reduction. For example, contemplated dosage of acompound of the present disclosure in the methods described herein mayinclude administering a dose independent of body weight of about 200mg/day, about 80 mg/day, about 40 mg/day, about 20 mg/day, about 10mg/day, about 5 mg/day, about 3 mg/day, about 2 mg/day, about 1 mg/day,about 0.5 mg/day, about 0.2 mg/day, about 0.05 mg/day, about 0.01mg/day, or about 0.001 mg/day.

An effective amount of the drug for tumor reduction in a patient mayalso be dosed based on body weight or surface area and be about 0.0001mg/kg to about 5 mg/kg of body weight per day. For example, acontemplated dosage may be from about 0.001 to 5 mg/kg of body weightper day, about 0.001 mg/kg to 1 mg/kg of body weight per day, about0.001 mg/kg to 0.1 mg/kg of body weight per day, about 0.001 to about0.010 mg/kg of body weight a day or about 0.007 mg/kg of body weight aday in single, divided, or continuous doses. These doses may be adjustedfor the patient's weight in kg, body surface area in m², and age inyears. For example, a contemplated dosage may be about 1 mg/m² to about50 mg/m², about 5 mg/m² to about 25 mg/m², about 5 mg/m² to about 50mg/m², about 5 mg/m² to about 15 mg/m², or about 5 mg/m² to about 10mg/m².

An effective amount of a pharmaceutical agent is that which provides anobjectively identifiable improvement as noted by the clinician or otherqualified observer. For example, regression of a tumor in a patient maybe measured with reference to the diameter of a tumor. Decrease in thediameter of a tumor indicates regression. Regression is also indicatedby failure of tumors to reoccur after treatment has stopped. As usedherein, the term “dosage effective manner” refers to amount of an activecompound to produce the desired biological effect in a subject or cell.

The dosage regimen utilizing the compounds is selected in accordancewith a variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to prevent, counteror arrest the progress of the condition.

Administration of a compound of the present disclosure in accordancewith the method in the present disclosure can be continuous orintermittent, depending, for example, upon the recipient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to skilled practitioners. Theadministration of a compound of the present disclosure may beessentially continuous over a preselected period of time or may be in aseries of spaced doses.

For repeated administrations over several days or longer, depending onthe condition, the treatment is sustained until a desired suppression ofdisease symptoms occurs or until sufficient therapeutic levels areachieved. For example, dosing from one to five times a week iscontemplated. Other dosing regimens include a regimen of, 1 to 5 timesper week, every three to four days, or less frequently. In certainaspects, a compound of the present disclosure is administered aboutevery fourth day, about every seventh day, about ever tenth day or aboutevery fourteenth day. In some aspects, a compound of the presentdisclosure is administered about once per week, once every two weeks, orabout 1 to 4 times per month depending on the duration of the responseto drug administration. Intermittent dosing regimen with staggereddosages spaced by 2 days up to 7 days or even 14 days may be used. Insome aspects, treatment may start with a daily dosing and later changeto weekly even monthly dosing. The progress of this therapy is easilymonitored by conventional techniques and assays, or by measuring MetAP2as described in U.S. Pat. No. 6,548,477.

Frequency of administration may be determined and adjusted over thecourse of therapy. For example, frequency of administration may bedetermined or adjusted based on the type and severity of the disease tobe treated, whether the agent is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the agent, and the discretion of the attendingphysician. Typically the clinician will administer a compound of thepresent disclosure until a dosage is reached that achieves the desiredresult

Treatment can be continued for as long or as short a period as desired.A suitable treatment period can be, for example, at least about oneweek, at least about four weeks, at least about one month, at leastabout six months, at least about 1 year, at least about 2 years, orindefinitely. A treatment period can terminate when a desired result,for example tumor reduction target, is achieved. For example, when lossof about 5% tumor size, about 10% tumor size, about 20% tumor size,about 30% tumor size or more has been achieved. A treatment regimen caninclude a corrective phase, during which a compound of the presentdisclosure is administered in dose, or dosing frequency, sufficient toprovide reduction of tumor size is administered, followed by amaintenance phase, during which a lower compound dose, or decreaseddosing frequency, sufficient to prevent tumor regrowth is administered.

Compounds and Pharmaceutical Compositions of the Present Disclosure

The present disclosure provides compositions and drug conjugatecompositions including an active moiety modified, a conjugate moiety,and a cleavable linker, wherein cleavage of the linker occurssubstantially in a target tissue to produce a modified active moietyhaving reduced efflux from target tissue compared to the unmodifiedactive moiety. The present disclosure also provides compositionsincluding a modified active moiety.

The conjugate moiety used depends on the physicochemical properties ofboth the conjugate moiety and the active moiety, in addition tobiological requirements, e.g., pharmacokinetic and pharmacodynamicproperties of the active moiety and knowledge of the disease state. Oneof skill in the art will be able to select an appropriate conjugatemoiety based upon the above considerations. The conjugate moiety may beused to deliver small molecule active moieties or larger molecule activemoieties, such as proteins, peptides, or oligonucleotides.

The conjugate moiety improves the delivery of an active moiety totarget. The conjugate moiety is chosen to maximize bioavailability ofthe active moiety, optimize onset, duration, and rate of delivery of theactive moiety, and maintain the concentration of an active moiety in atarget tissue within a therapeutic range as long as required foreffective treatment. The conjugate moiety may also assist in minimizingadverse side effects of an active moiety. Thus the conjugate moietyprolongs pharmacological activity of an active moiety, stabilizes labileactive moieties from chemical and proteolytic degradation, minimizesside effects, increases solubility, and targets the active moiety tospecific cells or tissues.

Other properties of the conjugate moiety to be considered are that theconjugate moiety is minimally or non-immunogenic and non-toxic. Themolecular weight of the conjugate moiety should be sufficiently large toavoid rapid elimination via kidney ultrafiltration and low enough toprevent undesirable accumulation within the body. In certain aspects,the conjugate moiety is hydrophilic and is biodegradable. Conjugatemoieties that are non-biodegradable are also suitable with compositionsand methods of the disclosure. The conjugate moiety should be able tocarry the required amount of active moiety and protect against prematuremetabolism of the active moiety in transit to the target tissue.

Exemplary conjugates include all forms of polymers, synthetic polymersas well as natural product related polymers including peptides,polysaccharides, polynucleic acids, antibodies and aptamers. Inpreferable aspects, the conjugate is a synthetic polymer. Exemplarypolymers of the disclosure have been described in U.S. Pat. No.4,997,878 to Bock et al, U.S. Pat. No. 5,037,883 to Kopecek et al. U.S.Pat. No. 5,258,453 to Kopecek et al., U.S. Pat. No. 6,464,850 to Zhanget al., U.S. Pat. No. 6,803,438 to Brocchini et al., each of which isincorporated by reference in its entirety. Additional exemplary polymershave been described in Subr et al., J Controlled Release, 18, 123-132(1992). In some aspects, the method of synthesis of the polymer may leadto the coupling of two or more polymer chains and may increase theweight average molecular weight of the polymer conjugate. It is furtherrecognized that if this coupling occurs, the linkages will bebiodegradable.

The active moiety may be any compound or molecule that produces atherapeutic effect in a subject. In certain aspects, the compound ormolecule has a molecular weight of 2000 Daltons or less, 1500 Daltons orless, 1000 Daltons or less, 500 Daltons or less, 250 Daltons or less,100 Daltons or less, 75 Daltons or less, 50 Daltons or less, or 25Daltons or less. In certain aspects, the compound or molecule is amethionine aminopeptidase-2 (MetAP2) inhibitor. In certain aspects, thecompound or molecule is fumagillin, fumagillol, or an analog,derivative, salt or ester thereof. The compound or molecule chosen willdepend on the condition or disease to be treated. In certain aspects,two or more active moieties may be used. In certain aspects an activemoiety and an inactive “capping” moiety may be used. In compositions ofthe disclosure, the conjugate moiety is joined to the active moiety viaa linker. Any linker structure known in the art may be used to join themodified active moiety to the conjugate moiety. The linker used willdepend on the physiological conditions of the target tissue, theproperties of the active moiety that are being optimized, and thecleavage mechanism. D'Souza et al. review various types of linkersincluding linkers that operate via proteolytic cleavage “Release fromPolymeric Prodrugs: Linkages and Their Degradation” J. Pharm. Sci., 93,1962-1979 (2004). Blencoe et al. describe a variety of self-immolativelinkers, “Self-immolative linkers in polymeric delivery systems” Polym.Chem. 2, 773-790 (2011). Ducry et al. review linkers in Bioconj. Chem.21, 5-13 (2010) “Antibody-Drug Conjugates: Linking Cytotoxic Payloads toMonoclonal Antibodies”. Peptide linkers suitable for cleavage by matrixmetalloproteinases (MMPs) are described in Chau et al. “Antitumorefficacy of a novel polymer-peptide-drug conjugate in human tumorxenograft models” Int. J. Cancer 118, 1519-1526 (2006) and Chau et al.U.S. patent publication number 2004/0116348. Other linker chemistriessuitable with compositions of the disclosure are shown in Shiose et al.Biol. Pharm. Bull. 30(12) 2365-2370 (2007); Shiose et al. BioconjugateChem. 20(1) 60-70 (2009); Senter, U.S. Pat. No. 7,553,816; De Groot,U.S. Pat. No. 7,223,837; King, U.S. Pat. No. 6,759,509; Susaki, U.S.Pat. No. 6,835,807; Susaki U.S. Pat. No. 6,436,912; and Gemeinhart U.S.Pat. No. 7,943,569.

In certain aspects, the linker is a peptide linker. Exemplary peptidelinkers are described in U.S. Pat. No. 6,835,807 to Susaki et al., U.S.Pat. No. 6,291,671 to Inoue et al., U.S. Pat. No. 6,811,996 to Inoue etal., U.S. Pat. No. 7,041,818 to Susaki et al., U.S. Pat. No. 7,091,186to Senter et al., U.S. Pat. No. 7,553,816 to Senter et al. each of whichis incorporated by reference in its entirety. Additional exemplarypeptides and their cleavage have been described in Shiose et al. Biol.Pharm. Bull. 30(12) 2365-2370 (2007) and Shiose et al. BioconjugateChem. 20(1) 60-70 (2009). Peptide linkers suitable for cleavage bymatrix metalloproteinases (MMPs) are described in Chau et al. “Antitumorefficacy of a novel polymer-peptide-drug conjugate in human tumorxenograft models” Int. J. Cancer 118, 1519-1526 (2006) and Chau et al.U.S. patent publication number 2004/0116348.

The linker may be cleaved by any mechanism known in the art. Forexample, the linkers may be designed for proteolytic cleavage orintracellular proteolytic cleavage. In certain aspects, the linker isdesigned such that there is no cleavage of the linker in plasma or thereis a very low rate of cleavage in the plasma. Exemplary linkerstructures are described in further detail below.

In certain aspects, the linker has a structure such that it is to bepreferentially cleaved in disease tissue. Since most hydrolases exist inboth normal and diseased tissue, the linker should be cleaved by ahydrolase that is more active in disease tissue and/or more prevalent indisease tissue. For example, tumors have generally upregulated metabolicrates and in particular over express proteases including the cathepsins.The upregulation and role of proteases in cancer is described by Masonet al. Trends in Cell Biology 21, 228-237 (2011).

In certain aspects, the class of active moieties that are modified aremoieties that irreversibly bind to their targets, i.e., after releasefrom the conjugate the active moiety covalently binds to the biochemicaltarget. Once bound, the active moiety cannot diffuse or be transportedout of the cell. For targeting to occur in the case of irreversiblebinding, the rate of small molecule binding to target, k_(rev1), shouldbe significant relative to the rate of small molecule efflux, k_(sm-1).If the rate of efflux is high relative to small molecule binding, smallmolecule equilibrium will be established between the plasma and theintracellular compartment and there will be no advantage tointracellular delivery relative to extracellular delivery.

In other aspects, the class of active moieties that are modified aremoieties that reversibly bind to their targets. For targeting to occurin the case of reversible binding, the equilibrium constant for smallmolecule binding to target K=k_(rev1)/k_(rev-1) should be large and the“on-rate”, k_(rev1), should be large relative to the rate of smallmolecule efflux, k_(sm-1). If the rate of efflux is high relative tosmall molecule binding, small molecule equilibrium will be establishedbetween the plasma and the intracellular compartment and there will beno advantage to intracellular delivery relative to extracellulardelivery. Such a relationship is described schematically below, where:[PC]=concentration of polymer conjugate; [SM]=concentration of releasedsmall molecule; plasma=plasma concentration; icell=intracellularconcentration; icell-target=small molecule reversibly bound tointracellular target; and inactive=inactive metabolite of smallmolecule. In certain aspects, when k_(rev-1)=zero, the moietyirreversibly binds to its target.

In other aspects, the class of active moieties that are modified aremoieties that have very high equilibrium constants and high “on-rates”relative to efflux. In other aspects, the class of active moieties thatare modified are moieties that undergo intracellular metabolism at ahigh rate relative to efflux.

In certain aspects, modifications to the active moiety are accomplishedby using a linker having a structure such that upon cleavage, a fragmentof the linker remains attached to the active moiety. That fragment maychange any of the molecular weight, hydrophobicity, polar surface area,or charge of the active moiety, thereby producing a modified activemoiety having reduced efflux from a target cell compared to theunmodified active moiety. For example, coupling MetAP2 inhibitory activemoieties via the linkers described herein provide conjugates in whichupon cleavage of the linker, produce an active moiety having a fragmentof the linker attached thereto (modified active moiety). The modifiedactive moieties described herein may have reduced efflux from a cellcompared to the unmodified active moieties, resulting in modified activemoieties with superior efficacy to the parent small molecules andsuperior efficacy to the parent small molecules and superiorpharmacokinetic profiles.

The present disclosure provides conjugates with linkers having thestructure:

wherein, independently for each occurrence, R₄ is H or C₁-C₆ alkyl; R₅is H or C₁-C₆ alkyl; R₆ is C₂-C₆ hydroxyalkyl; Z is—NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-L or—NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-Q-X-Y-C(O)—W; AA₁ is glycine, alanine,or H₂N(CH₂)mCO₂H, wherein m is 2, 3, 4 or 5; AA₂ is a bond, or alanine,cysteine, aspartic acid, glutamic acid, phenylalanine, glycine,histidine, isoleucine, lysine, leucine, methionine, asparagine, proline,glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;AA₃ is a bond, or alanine, cysteine, aspartic acid, glutamic acid,phenylalanine, glycine, histidine, isoleucine, lysine, leucine,methionine, asparagine, proline, glutamine, arginine, serine, threonine,valine, tryptophan, or tyrosine; AA₄ is a bond, or alanine, cysteine,aspartic acid, glutamic acid, phenylalanine, glycine, histidine,isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine,arginine, serine, threonine, valine, tryptophan, or tyrosine; AA₅ is abond, or glycine, valine, tyrosine, tryptophan, phenylalanine,methionine, leucine, isoleucine, or asparagine; AA₆ is a bond, oralanine, asparagine, citrulline, glutamine, glycine, leucine,methionine, phenylalanine, serine, threonine, tryptophan, tyrosine,valine, or H₂N(CH₂)mCO₂H, wherein m is 2, 3, 4 or 5; L is —OH,—O-succinimide, —O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, —NH₂, —NH(C₂-C₆ hydroxyalkyl),halide or perfluoroalkyloxy; Q is NR, O, or S; X isM-(C(R)₂)_(p)-M-J-M-(C(R)₂)_(p)-M-V; M is a bond, or C(O); J is a bond,or ((CH₂)_(q)Q)_(r), C₅-C₈ cycloalkyl, aryl, heteroaryl, NR, O, or S; Yis NR, O, or S; R is H or alkyl; V is a bond or

R⁹ is alkyl, aryl, aralkyl, or a bond; or R⁹ taken together with Y formsa heterocyclic ring; R¹⁰ is amido or a bond; R¹¹ is H or alkyl; W is aMetAP2 inhibitor moiety or alkyl; x is in the range of 1 to about 450; yis in the range of 1 to about 30; n is in the range of 1 to about 100; pis 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4, 5, or 6. In some aspects,n is in the range of about 1 to about 90; about 1 to about 80; about 1to about 70; about 1 to about 60; about 1 to about 55; or about 1 toabout 50.

In certain aspects, R₄ is C₁-C₆ alkyl. In certain aspects, R₄ is methyl.In certain aspects, R₅ is C₁-C₆ alkyl. In certain aspects, R₅ is methyl.In certain aspects, R₆ is 2-hydroxyethyl, 2-hydroxypropyl or3-hydroxypropyl. In certain aspects, R₆ is 2-hydroxypropyl.

In certain aspects, the compound has a molecular weight of greater thanabout 100 kDa. In certain aspects, the compound has a molecular weightof less than about 100 kDa. In other aspects, the molecular weight isless than about 95 kDa. In other aspects, the molecular weight is lessthan about 90 kDa. In other aspects, the molecular weight is less thanabout 80 kDa. In other aspects, the molecular weight is less than about70 kDa. In other aspects, the molecular weight is less than about 65kDa. In other aspects, the molecular weight is less than about 60 kDa.In other aspects, the molecular weight is less than about 45 kDa. Inother aspects, the molecular weight is less than about 35 kDa.

In certain aspects, the ratio of x to y is in the range of about 100:1to about 1:1. In certain aspects, the ratio of x to y is in the range ofabout 30:1 to about 3:1. In other aspects, the ratio of x to y is in therange of about 19:2 to about 7:2. In certain aspects, the ratio of x toy is in the range of about 9:1 to about 4:1. In certain aspects, theratio of x to y is about 11:1. In certain aspects, the ratio of x to yis about 9:1. In certain aspects, the ratio of x to y is about 4:1. Incertain aspects, the ratio of x to y is about 12:1. For example, incertain aspects, the ratio of x:y is about 3:1; the ratio of x:y isabout 4:1; the ratio of x:y is about 5:1; the ratio of x:y is about 6:1;the ratio of x:y is about 7:1; the ratio of x:y is about 8:1; the ratioof x:y is about 9:1; the ratio of x:y is about 10:1; the ratio of x:y isabout 11:1; the ratio of x:y is about 12:1; the ratio of x:y is about13:1; the ratio of x:y is about 14:1; the ratio of x:y is about 15:1;the ratio of x:y is about 16:1; the ratio of x:y is about 17:1; theratio of x:y is about 18:1; the ratio of x:y is about 19:1; the ratio ofx:y is about 20:1; the ratio of x:y is about 21:1; the ratio of x:y isabout 22:1; the ratio of x:y is about 23:1; the ratio of x:y is about24:1; the ratio of x:y is about 25:1; the ratio of x:y is about 26:1;the ratio of x:y is about 27:1; the ratio of x:y is about 28:1; theratio of x:y is about 29:1; or the ratio of x:y is about 30:1.

In certain aspects, Z is —NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-L. In certainaspects, L is methoxy, ethoxy, pentafluorophenyloxy, phenyloxy, acetoxy,fluoride, chloride, methoxycarbonyloxy; ethoxycarbonyloxy,phenyloxycarbonyloxy, 4-nitrophenyloxy, trifluoromethoxy,pentafluoroethoxy, or trifluoroethoxy. In certain aspects, L is4-nitrophenyloxy.

In certain aspects, Z is —NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-Q-X—Y—C(O)—W.In certain aspects, AA₁ is glycine. In certain aspects, AA₂ is glycine.In certain aspects, AA₃ is glycine. In certain aspects, AA₄ is glycineor phenylalanine In certain aspects, AA₅ is leucine, phenylalanine,valine or tyrosine. In certain aspects, AA₆ is asparagine, citrulline,glutamine, glycine, leucine, methionine, threonine or tyrosine. Incertain aspects, AA₅-AA₆ is Leu-Cit, Leu-Gln, Leu-Gly, Leu-Leu, Leu-Met,Leu-Thr, Phe-Cit, Phe-Gln, Phe-Leu, Phe-Met, Phe-Thr, Val-Asn, Val-Cit,Val-Gln, Val-Leu, Val-Met, Val-Thr, Tyr-Cit, Tyr-Leu, or Tyr-Met. Incertain aspects, AA₁, AA₃ and AA₅ are glycine, valine, tyrosine,tryptophan, phenylalanine, methionine, leucine, isoleucine, orasparagine. In certain aspects, AA₂, AA₄ and AA₆ are glycine,asparagine, citrulline, glutamine, glycine, leucine, methionine,phenylalanine, threonine or tyrosine. In certain aspects, AA₂ is a bond;and AA₃ is a bond. In certain aspects, AA₁ is glycine; AA₄ isphenylalanine; AA₅ is leucine; and AA₆ is glycine.

In certain aspects, W is

wherein R₂ is —OH or methoxy; and R₃ is H, —OH or methoxy.

In certain aspects, W is

In certain aspects, W is

In certain aspects, Q is NR. In other aspects, Q is S.

In certain aspects, J is NR. In other aspects, J is ((CH₂)_(q)Q)_(r). Inother aspects, J is C₅-C₈ cycloalkyl. In certain aspects, J is aryl.

In certain aspects, Y is NR. In other aspects, Y is S.

In certain aspects, -Q-X—Y— is

V is:

or a bond; R¹² is H or Me; or R¹² taken together with R¹⁴ forms apiperidine ring; R¹¹ is H or Me; and R¹³ taken together with R¹² forms apiperidine ring.

In certain aspects, -Q-X—Y— is

In certain aspects, -Q-X—Y— is

In certain aspects, -Q-X—Y— is

In certain aspects, -QXY is

In certain aspects, -Q-X—Y— is

In certain aspects, -Q-X—Y— is

In certain aspects, R₄ and R₅ are methyl; R₆ is 2-hydroxypropyl; Z is—NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-Q-X—Y—C(O)—W; AA₁ is glycine; AA₂ is abond; AA₃ is a bond; AA₄ is phenylalanine; AA₅ is leucine; AA₆ isglycine; -Q-X—Y— is

and W is

In certain aspects, R₄ and R₅ are methyl; R₆ is 2-hydroxypropyl; Z is—NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-Q-X—Y—C(O)—W; AA₁ is glycine; AA₂ is abond; AA₃ is a bond; AA₄ is phenylalanine; AA₅ is leucine; AA6 isglycine; -Q-X—Y— is

and W is

In certain aspects, R₄ and R₅ are methyl; R₆ is 2-hydroxypropyl; Z is—NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-Q-X—Y—C(O)—W; AA₁ is glycine; AA₂ is abond; AA₃ is a bond; AA₄ is phenylalanine; AA₅ is leucine; AA₆ isglycine; -Q-X—Y— is

and W is

In certain aspects, R₄ and R₅ are methyl; R₆ is 2-hydroxypropyl; Z is—NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-Q-X—Y—C(O)—W; AA₁ is glycine; AA₂ is abond; AA₃ is a bond; AA₄ is phenylalanine; AA₅ is leucine; AA₆ isglycine; -Q-X—Y—is

and W is

In certain aspects, -Q-X—Y— is a self-immolating linker that releasesthe MetAP2 inhibitor in the form of a carbamate derivative, as shown inthe scheme below:

Another aspect of the present disclosure provides conjugates withlinkers having the structure: Z-Q-X—Y—C(O)—W; wherein, independently foreach occurrence, Z is H₂N-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)— or H; AA₂ is a bond,or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine,glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine,proline, glutamine, arginine, serine, threonine, valine, tryptophan, ortyrosine; AA₃ is a bond, or alanine, cysteine, aspartic acid, glutamicacid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine,methionine, asparagine, proline, glutamine, arginine, serine, threonine,valine, tryptophan, or tyrosine; AA₄ is a bond, or alanine, cysteine,aspartic acid, glutamic acid, phenylalanine, glycine, histidine,isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine,arginine, serine, threonine, valine, tryptophan, or tyrosine; AA₅ is abond, alanine, cysteine, glycine, isoleucine, leucine, methionine,phenylalanine, valine, tryptophan, or; AA₆ is alanine, asparagine,citrulline, glutamine, glycine, leucine, methionine, phenylalanine,serine, threonine, tryptophan, tyrosine, valine or H₂N(CH₂)mCO₂H,wherein m is 2, 3, 4 or 5; Q is NR, O, or S; X isM-(C(R)₂)_(p)-M-J-M-(C(R)₂)_(p)-M-V; M is a bond, or C(O); J is a bond,or ((CH₂)_(q)Q)_(r), C₅-C₈ cycloalkyl, aryl, heteroaryl, NR, O, or S; Yis NR, O, or S; R is H or alkyl; V is a bond or

R⁹ is alkyl, aryl, aralkyl, or a bond; or R⁹ taken together with Y formsa heterocyclic ring; R¹⁰ is amido or a bond; R¹¹ is H or alkyl; W is aMetAP2 inhibitor moiety; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4,5, or 6.

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—. In certain aspects, AA₅ isalanine, cysteine, glycine, isoleucine, leucine, methionine,phenylalanine, valine, tryptophan, or tyrosine and AA₆ is glycine. Incertain aspects, AA₅ is leucine and AA₆ is glycine. In certain aspects,AA₅ is valine and AA₆ is glycine. In certain aspects, AA₅ isphenylalanine and AA₆ is glycine. In certain aspects, AA₅ is glycine andAA₆ is glycine. In certain aspects, AA₅ is not valine.

In other aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—. In certain aspects,AA₅ is alanine, cysteine, glycine, isoleucine, leucine, methionine,phenylalanine, valine, tryptophan, or tyrosine and each of AA₃, AA₄, orAA₆ is glycine. In certain aspects, AA₅ is leucine and each of AA₃, AA₄,or AA₆ is glycine. In certain aspects, AA₅ is valine and each of AA₃,AA₄, or AA₆ is glycine. In certain aspects, AA₅ is phenylalanine andeach of AA₃, AA₄, or AA₆ is glycine. In certain aspects, AA₃ is glycine,AA₄ is phenylalanine, AA₅ is leucine and AA₆ is glycine. In certainaspects, each of AA₃, AA₄, AA₅ and AA₆ is glycine. In certain aspects,AA₅ is not valine.

In certain aspects, Z is H. In other aspects, Z is H₂N-AA₆-C(O)—. Incertain aspects, AA₆ is glycine.

In certain aspects, Q is NR. In certain aspects, M is a bond. In certainaspects, J is a bond. In certain aspects, Y is NR.

In certain aspects, W is:

wherein R₂ is —OH or methoxy; and R₃ is H, —OH or methoxy.

In certain aspects, W is

In certain aspects, W is

In certain aspects, -Q-X—Y— is

V is:

or a bond; R¹² is H or Me; or R¹² taken together with R¹⁴ forms apiperidine ring; R¹¹ is H or Me; and R¹³ taken together with R¹² forms apiperidine ring.

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is leucine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is valine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is phenylalanine and AA₆is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is glycine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is leucine andeach of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is valine andeach of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is phenylalanineand each of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₃ is glycine, AA₄is phenylalanine, AA₅ is leucine and AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; each of AA₃, AA₄,AA₅ and AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₆-C(O)—; AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is leucine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is valine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is phenylalanine and AA₆is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is glycine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is leucine andeach of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is valine andeach of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is phenylalanineand each of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₃ is glycine, AA₄is phenylalanine, AA₅ is leucine and AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; each of AA₃, AA₄,AA₅ and AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₆-C(O)—; AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is leucine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is valine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is phenylalanine and AA₆is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is glycine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is leucine andeach of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is valine andeach of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is phenylalanineand each of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₃ is glycine, AA₄is phenylalanine, AA₅ is leucine and AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; each of AA₃, AA₄,AA₅ and AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₆-C(O)—; AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is leucine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is valine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is phenylalanine and AA₆is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₅-AA₆-C(O)—; AA₅ is glycine and AA₆ isglycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is leucine andeach of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is valine andeach of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₅ is phenylalanineand each of AA₃, AA₄, or AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; AA₃ is glycine, AA₄is phenylalanine, AA₅ is leucine and AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—; each of AA₃, AA₄,AA₅ and AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H₂N-AA₆-C(O)—; AA₆ is glycine; Q-X—Y is

and W is

In certain aspects, Z is H; Q-X—Y is

and W is

Other active moieties that may be modified to be used in conjugates ofthe disclosure include the following structures:

In certain aspects, the active moiety is an anti-tumor compound. Inother aspects, the active moiety is a molecule that inhibits methionineaminopeptidase-2 (MetAP2), such as fumagillin, fumagillol, or an analog,derivative, salt or ester thereof. MetAP2 is a co-translational enzymeresponsible for cleaving the initiator methionine off nascentpolypeptides. It has several exclusive substrates that tend to beup-regulated under conditions of cellular stress, hypoxia and when cellsare dividing. Fumagillin is a natural product derived from the biomassof the fungus Aspergillus Fumigatus Fresenius. Fumagillin and itsderivatives are known to inhibit the aminopeptidase activity of MetAP2.Further exemplary MetAP2 inhibitors have been described in U.S. Pat. No.6,242,494 to Craig et al, U.S. Pat. No. 6,063,812 to Hong et al., U.S.Pat. No. 6,887,863 to Craig et al., U.S. Pat. No. 7,030,262 to BaMaunget al., U.S. Pat. No. 7,491,718 to Comess et al., each of which isincorporated by reference in its entirety. Additional exemplary MetAP2inhibitors have been described in Wang et al. “Correlation of tumorgrowth suppression and methionine aminopeptidase-2 activity blockadeusing an orally active inhibitor,” PNAS 105(6) 1838-1843 (2008); Lee atal. “Design, Synthesis, and Antiangiogenic Effects of a Series of PotentNovel Fumagillin Analogues,” Chem. Pharm. Bull. 55(7) 1024-1029 (2007);Jeong et al. “Total synthesis and antiangiogenic activity ofcyclopentane analogues of fumagillol,” Bioorganic and MedicinalChemistry Letters 15, 3580-3583 (2005); Arico-Muendel et al. “CarbamateAnalogues of Fumagillin as Potent, Targeted Inhibitors of MethionineAminopeptidase-2,” J. Med. Chem. 52, 8047-8056 (2009); and InternationalPublication No. WO 2010/003475 to Heinrich et al.

Fumagillin is a small molecule which has been used as an antimicrobialand antiprotozoal agent. Its physiochemical properties and method ofproduction are well known (See U.S. Pat. No. 2,803,586 and Turner, J. R.et al., The Stereochemistry of Fumagillin, Proc. Natl. Acad. Sci. 48,733-735 (1962)). The fermentation product, fumagillin, may be hydrolyzedto yield the alcohol fumagillol which in turn may be converted intovarious derivatives including carbamoylfumagillol, MW 325. The synthesisand preparation of carbamoylfumagillol and some small moleculederivatives are described in U.S. Pat. No. 5,166,172.

Fumagillin and related compounds are believed to exert their biologicaleffects through the inhibition of MetAP2. This enzyme removes N-terminalmethionine from nascent cellular proteins. (See Tucker, L. A., et al.“Ectopic Expression of Methionine Aminopeptidase-2 Causes CellTransformation and Stimulates Proliferation”, Oncogene 27, 3967 (2008).)

Carbamoylfumagillol and derivatives as well as other inhibitors ofMetAP2 have shown therapeutic benefits in preclinical and clinicalstudies. These compounds inhibit cell proliferation and angiogenesis asdescribed in U.S. Pat. No. 5,166,172. Fumagillin analogs or derivatives,such as CKD-732 and PI-2458, are well studied in various systems asdescribed in detail in Bernier et al., “Fumagillin class inhibitors ofmethionine aminopeptidase-2” Drugs of the Future 30(5): 497-508, 2005.

The anti-obesity effects of fumagillin and its analogs are well-known.Rupnick et al. “Adipose tissue mass can be regulated through thevasculature” PNAS 99, 10730-10735, 2002 describes weight loss in ob/obmice with daily doses of TNP-470 ranging from 2.5 mg/kg to 10 mg/kg.Brakenhielm describes prevention of obesity at TNP-470 doses of 15 or 20mg/kg every other day, “The Angiogenesis Inhibitor, TNP-470, PreventsDiet-Induced and Genetic Obesity in Mice” Circulation Research 94:1579-1588, 2004. Kim, et al., in the “Assessment of the anti-obesityeffects of the TNP-470 analog, CKD-732” J Molecular Endocrinology 38,455-465, 2007 describe weight loss in C57BL/6J mice and SD rats at dosesof 5 mg/kg/day. Lijnen et al. “Fumagillin reduces adipose tissueformation in murine models of nutritionally induced obesity” Obesity 12,2241-2246, 2010 describes oral delivery of 1 mg/kg fumagillin dailyresulting in weight loss in C57BL/6 mice.

One of these derivatives, chloroacetylcarbamoylfumagillol (TNP-470) hasbeen extensively studied. (See H Mann-Steinberg, et al., “TNP-470: TheResurrection of the First Synthetic Angiogenesis Inhibitor”, Chapter 35in Folkman and Figg, Angiogenesis: An Integrative Approach from Scienceto Medicine, Springer N.Y. (2008).) TNP-470 has shown activity againstmany cancers including lung cancer, cervical cancer, ovarian cancer,breast cancer and colon cancer. Because of dose-limiting neurotoxicity,TNP-470 has been tested using multiple dosing regimens, but theseattempts to limit its toxicity have been unsuccessful. Thus, TNP-470 hasbeen found to be too toxic for human use. TNP-470 has a short half-lifeand requires extended intravenous administration for therapeutic use. Ametabolite of TNP-470, carbamoylfumagillol has a half-life of 12 minutesin man. (See Herbst et al., “Safety and Pharmacokinetic Effects ofTNP-470, an Angiogenesis Inhibitor, Combined with Paclitaxel in Patientswith Solid Tumors: Evidence for Activity in Non-Small-Cell Lung Cancer”,Journal of Clinical Oncology 20(22) 4440-4447 (2002). In addition,fumagillin and its derivatives are hydrophobic and difficult toformulate.

Despite the known usefulness of fumagillin derivatives, they have notbeen used successfully as treatments because of the failure to overcomethe problems of the low water solubility, short half-life values, andneurotoxic side-effects of these compounds. TNP-470 in combination withpaclitaxel was determined to have an MTD of 60 mg/m2 dosed three timesper week based on the previously observed dose limiting neuropsychiatrictoxicities Herbst et al., “Safety and pharmacokinetic effects ofTNP-470, an angiogenesis inhibitor, combined with paclitaxel in patientswith solid tumors: evidence for activity in non-small-cell lung Cancer”Journal of Clinical Oncology 20, 4440-4447, 2002. Similarly Shin et al.“A Phase 1 pharmacokinetic and pharmacodynamics study of CKD-732, anantiangiogenic agent, in patients with refractory solid cancer”Investigational New Drugs 28, 650-658, 2010 reports that the MTD ofCKD-732 was 15 mg/m2/day dosed on an every fourth day schedule due toconfusion and insomnia. Accordingly, the compounds of the presentdisclosure are more potent, show reduced toxicity (less neurotoxic),improved water solubility, more stable, and/or have longer half-life(serum half-life) than presently known fumagillin derivatives.

The phrase “reduced toxicity” as used herein has its ordinary meaning asunderstood by persons of skill in the art. Merely by way of example, andby no means as a limitation on the meaning of the term, theadministration of the fumagillin analog conjugate causes less sideeffects in open field tests with mice, as compared to the fumagillinanalog alone.

The phrase “improved water solubility” has its ordinary meaning asunderstood by persons of skill in the art. Merely by way of example, andby no means as a limitation on the meaning of the term, the followingdescription of the term is informative: an increased amount of afumagillin analog will dissolve in water as a result of its covalentincorporation into a conjugate as compared to the amount of theunconjugated fumagillin analog that will dissolve in water alone.

The phrase “longer half-life” has its ordinary meaning as understood bypersons of skill in the art. Merely by way of example, and by no meansas a limitation on the meaning of the term, the following description ofthe term is informative: any appreciable increase in the length of timerequired to deactivate fumagillin conjugate either in vivo or in vitroas compared to the half-life of the fumagillin analog alone either invivo or in vitro.

Without being bound by any theory, non-enzymatic actions of MetAP2 tosuppress activity of extra-cellular signal regulated kinases 1 and 2(ERK1/2) may be important as may be the binding of eukaryotic initiationfactor, eIF, by MetAP2. Cellular responses to MetAP2 inhibitionreflective of potential ERK-related processes may include suppression ofsterol regulatory element binding protein (SREBP) activity, leading toreduced lipid and cholesterol biosynthesis. Interesting, changes in theexpression patterns of hepatic and adipose tissue genes after prolonged(approximately 9 months) fumagillin exposure suggest that MetAP2inhibition also may alter the relative abundance of factors involved ininflammation, consistent with reduced ERK-dependent cellular processes.The putative mechanism of MetAP2 inhibition leading to mobilization ofadipose depot and catabolism of free fatty acids as energy source by thebody is supported by changes in plasma β-hydroxybutyrate, adiponectin,leptin, and FGF21 observed in previous studies. Elevation in the levelsof key catabolic hormones adiponectin and FGF21, coupled with theappearance of ketone bodies (β-hydroxybutyrate), suggest MetAP2inhibition with the conjugated or modified fumagillin, fumagillol, or ananalog, derivative, salt or ester thereof compounds of the presentdisclosure stimulates energy expenditure, fat utilization and lipidexcretion. The reduction in leptin observed in previous studies and thestudies provided herein is also consistent with a decrease in totaladipose tissue and negative energy balance. It is also possible that theconjugated or modified fumagillin, fumagillol, or an analog, derivative,salt or ester thereof compounds of the present disclosure form acovalent bond with MetAP2, thereby irreversibly inhibiting and silencingexisting enzyme until a newly produced pool of MetAP2 is generated intarget tissues (e.g., liver and adipose tissue).

In certain aspects, the conjugated or modified fumagillin, fumagillol,or an analog, derivative, salt or ester thereof compounds of the presentdisclosure, for example have the following formula as shown in Table 1:

TABLE 1 Com- pound No. Chemical Structure 5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

* wherein Polymer has the structure of:

and preferably the structure of:

In some aspects, the compound is:

In some aspects, the compound is:

In some aspects, the compound is:

In some aspects, the compound is:

In some aspects, the compound is:

In some aspects, the compound is:

In one or more aspects, a compound for use in the present disclosure canbe selected fromcis-(3aRS,9bRS)-7-(benzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylicacid;cis-(3aRS,9bRS)-7-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylicacid;cis-(3aRS,9bRS)-7-[2-(3-{pyrrolidin-1-yl}propyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylicacid;cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylicacid;cis-(3aR,9bR)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluoro-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylicacid;cis-(3aS,9bS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylicacid;7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylicacid formate salt;7-(benzenesulfonylamino))-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylicacid formate salt;cis-(3aRS,9bRS)-7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylicacid; (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid;(1aRS,7bSR)-5-[2-((E)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;cis-(3aRS,9bRS)-7-[2-(4-dimethylamino-butylamino)-benzenesulfonylamino]-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylicacid; (1aR,7bS)-5-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aS,7bR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid; (1 aS,7bR)-5-{2[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-(3-dimethylaminopropylamino)-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aR,7bS)-5-[2-(3-dimethylaminopropylamino)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aS,7bR)-5-[2-(3-dimethylaminopropyl-amino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-(4-dimethylamino-butylamino)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aS,7bR)-5-[2-(4-dimethylaminobutylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-[2-(5-dimethylamino-pentylamino)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2[(Z)-3-(propan-2-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2[(Z)-3-((S)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2[(Z)-3-((R)-3-hydroxypyrrolidin-1-yl)aminoprop-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aS,7bR)-5-[2((Z)-4-diethylaminobut-1-enyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[2-(4-ethylpiperazin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)prop-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2[(Z)-3-(3-hydroxy-azetidin-1-yl)prop-1-enyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2[(Z)-3-(azetidin-1-yl)propyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-[2((Z)-4-diethylaminobutyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[N-(4-dimethylaminobutyl)-N-methylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)-methyl]-4-fluoro-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[2-(pyrrolidin-1-yl)-ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aS,7bR)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid; (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-2-yl)carbonyl-aminomethyl]-4-fluorobenzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-((S)-1-ethyl-pyrrolidin-3-ylmethyl)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-(3-dimethylaminopropylcarbamoyl)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-(2-{[N-((S)-1-ethyl-pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-(2-{[N-((R)-1-ethyl-pyrrolidin-3-yl)-N-methylcarbamoyl]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-(3-N,N,-diethylaminopropylamino)benzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-2-yl)carbonyl-amino]methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2-[(1-ethylazetidin-3-ylmethyl)amino]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aS,7bR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aR,7bS)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1 aRS,7b SR)-5-(2-{N-[((R)-1-ethylpyrrolidine-2-yl)carbonyl]-N-methyl-aminomethyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-(2-{N-[((S)-1-ethylpyrrolidine-2-yl)carbonyl]-N-methylamino-methyl}-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-[2-(4-dimethylaminobutylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylmethyl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[2-(1-ethylazetidin-3-yl)ethyl]-4-fluoro-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[((S)-1-azabicyclo[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[((R)-1-azabicyclo-[2.2.2]oct-3-yl)amino]benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-(2-{[((S)-1-ethylpyrrolidine-3-carbonyl)amino]methyl}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluoro-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[((R)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-yl)amino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-(2-{[((R)-1-ethylpyrrolidine-3-carbonyl)amino]-methyl)}-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-[2-((Z)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid; (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-3-yl)ethylamino]-benzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-((S)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid; (1aR,7bS)-5-[2-((R)-1-ethylpyrrolidin-3-yloxymethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid;(1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylicacid;(1aR,7bS)-5-{2-[2-((R)-1-ethylpyrrolidin-2-yl)ethyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylicacid; and pharmaceutically acceptable salts, stereoisomers, esters andprodrugs thereof.

In one or more aspects, the compound is selected from:

and pharmaceutically acceptable salts or stereoisomers thereof.

For purposes of this disclosure, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

The term “alkyl” refers to a fully saturated branched or unbranchedcarbon chain radical having the number of carbon atoms specified, or upto 30 carbon atoms if no specification is made. For example, a “loweralkyl” refers to an alkyl having from 1 to 10 carbon atoms, such asmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, andthose which are positional isomers of these alkyls. Alkyl of 10 to 30carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl,pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl,heneicosyl, docosyl, tricosyl and tetracosyl. In certain aspects, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C₁-C₃₀ for straight chains, C₃-C₃₀ for branchedchains), and more preferably 20 or fewer. Likewise, certain cycloalkylshave from 3-10 carbon atoms in their ring structure, and may have 5, 6,or 7 carbons in the ring structure.

Unless the number of carbons is otherwise specified, “lower alkyl”, asused herein, means an alkyl group, as defined above, but having from oneto ten carbons, or from one to six carbon atoms in its backbonestructure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl”have similar chain lengths. Throughout the application, certain alkylgroups are lower alkyls. In certain aspects, a substituent designatedherein as alkyl is a lower alkyl.

The term “carbocycle”, as used herein, refers to an aromatic ornon-aromatic ring in which each atom of the ring is carbon.

The term “aryl” as used herein includes 5-, 6- and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole,oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazineand pyrimidine, and the like. Those aryl groups having heteroatoms inthe ring structure may also be referred to as “aryl heterocycles” or“heteroaromatics”. The aromatic ring can be substituted at one or morering positions with such substituents as described above, for example,halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl,alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic orheteroaromatic moieties, —CF₃, —CN, or the like. The term “aryl” alsoincludes polycyclic ring systems having two or more cyclic rings inwhich two or more carbons are common to two adjoining rings (the ringsare “fused rings”) wherein at least one of the rings is aromatic, e.g.,the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls,aryls and/or heterocyclyls.

“Alkenyl” refers to any branched or unbranched unsaturated carbon chainradical having the number of carbon atoms specified, or up to 26 carbonatoms if no limitation on the number of carbon atoms is specified; andhaving 1 or more double bonds in the radical. Alkenyl of 6 to 26 carbonatoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl,heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl,docosenyl, tricosenyl and tetracosenyl, in their various isomeric forms,where the unsaturated bond(s) can be located anywhere in the radical andcan have either the (Z) or the (E) configuration about the doublebond(s).

The term “alkynyl” refers to hydrocarbyl radicals of the scope ofalkenyl, but having one or more triple bonds in the radical.

The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group,as defined below, having an oxygen radical attached thereto.Representative alkoxy groups include methoxy, ethoxy, propoxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH₂)_(m)—R₁,where m and R₁ are described below.

The terms “heterocyclyl” or “heterocyclic group” refer to 3- to10-membered ring structures, more preferably 3- to 7-membered rings,whose ring structures include one to four heteroatoms. Heterocycles canalso be polycycles. Heterocyclyl groups include, for example, thiophene,thianthrene, furan, pyran, isobenzofuran, chromene, xanthene,phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,indole, indazole, purine, quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,phenanthroline, phenazine, phenarsazine, phenothiazine, furazan,phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine,piperazine, morpholine, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. The heterocyclic ringcan be substituted at one or more positions with such substituents asdescribed above, as for example, halogen, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl,sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde,ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN,or the like.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. In certain aspects, the “alkylthio”moiety is represented by one of —(S)-alkyl, —(S)-alkenyl, —(S)-alkynyl,and —(S)—(CH₂)_(m)—R₁, wherein m and R₁ are defined below.Representative alkylthio groups include methylthio, ethylthio, and thelike.

As used herein, the term “nitro” means —NO₂; the term “halogen”designates F, Cl, Br or I; the term “sulfhydryl” means —SH; the term“hydroxyl” means —OH; and the term “sulfonyl” means —SO₂—.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that can berepresented by the general formulae:

wherein R₃, R₅ and R₆ each independently represent a hydrogen, an alkyl,an alkenyl, —(CH₂)_(m)—R₁, or R₃ and R₅ taken together with the N atomto which they are attached complete a heterocycle having from 4 to 8atoms in the ring structure; R₁ represents an alkenyl, aryl, cycloalkyl,a cycloalkenyl, a heterocyclyl or a polycyclyl; and m is zero or aninteger in the range of 1 to 8. In certain aspects, only one of R₃ or R₅can be a carbonyl, e.g., R₃, R₅ and the nitrogen together do not form animide. In certain aspects, R₃ and R₅ (and optionally R₆) eachindependently represent a hydrogen, an alkyl, an alkenyl, or—(CH₂)_(m)—R₁. Thus, the term “alkylamine” as used herein means an aminegroup, as defined above, having a substituted or unsubstituted alkylattached thereto, i.e., at least one of R₃ and R₅ is an alkyl group. Incertain aspects, an amino group or an alkylamine is basic, meaning ithas a pK_(a)≧7.00. The protonated forms of these functional groups havepK_(a)s relative to water above 7.00.

The term “carbonyl” (C(O)) is art-recognized and includes such moietiesas can be represented by the general formula:

wherein X is a bond or represents an oxygen or a sulfur, and R₇represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R₁ or apharmaceutically acceptable salt, R₈ represents a hydrogen, an alkyl, analkenyl or —(CH₂)_(m)—R₁, where m and R₁ are as defined above. Where Xis an oxygen and R₇ or R₈ is not hydrogen, the formula represents an“ester”. Where X is an oxygen, and R₇ is as defined above, the moiety isreferred to herein as a carboxyl group, and particularly when R₇ is ahydrogen, the formula represents a “carboxylic acid”. Where X is anoxygen, and R₈ is hydrogen, the formula represents a “formate”. Ingeneral, where the oxygen atom of the above formula is replaced bysulfur, the formula represents a “thiocarbonyl” group. Where X is asulfur and R₇ or R₈ is not hydrogen, the formula represents a“thioester” group. Where X is a sulfur and R₇ is hydrogen, the formularepresents a “thiocarboxylic acid” group. Where X is a sulfur and R₈ ishydrogen, the formula represents a “thioformate” group. On the otherhand, where X is a bond, and R₇ is not hydrogen, the above formularepresents a “ketone” group. Where X is a bond, and R₇ is hydrogen, theabove formula represents an “aldehyde” group.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described herein above. The permissible substituentscan be one or more and the same or different for appropriate organiccompounds. For purposes of this disclosure, the heteroatoms such asnitrogen may have hydrogen substituents and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalences of the heteroatoms. This disclosure is not intended to belimited in any manner by the permissible substituents of organiccompounds. It will be understood that “substitution” or “substitutedwith” includes the implicit proviso that such substitution is inaccordance with permitted valence of the substituted atom and thesubstituent, and that the substitution results in a stable compound,e.g., which does not spontaneously undergo transformation such as byrearrangement, cyclization, elimination, etc.

The term “sulfamoyl” is art-recognized and includes a moiety that can berepresented by the general formula:

in which R₃ and R₅ are as defined above.

The term “sulfate” is art recognized and includes a moiety that can berepresented by the general formula:

in which R₇ is as defined above.

The term “sulfamido” is art recognized and includes a moiety that can berepresented by the general formula:

in which R₂ and R₄ are as defined above.

The term “sulfonate” is art-recognized and includes a moiety that can berepresented by the general formula:

in which R₇ is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The terms “sulfoxido” or “sulfinyl”, as used herein, refers to a moietythat can be represented by the general formula:

in which R₁₂ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

Analogous substitutions can be made to alkenyl and alkynyl groups toproduce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls,amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls.

As used herein, the definition of each expression, e.g., alkyl, m, n,etc., when it occurs more than once in any structure, is intended to beindependent of its definition elsewhere in the same structure.

The term “amino acid” is intended to embrace all compounds, whethernatural or synthetic, which include both an amino functionality and anacid functionality, including amino acid analogs and derivatives. Incertain aspects, the amino acids contemplated in the present disclosureare those naturally occurring amino acids found in proteins, or thenaturally occurring anabolic or catabolic products of such amino acids,which contain amino and carboxyl groups. Naturally occurring amino acidsare identified throughout by the conventional three-letter and/orone-letter abbreviations, corresponding to the trivial name of the aminoacid, in accordance with the following list. The abbreviations areaccepted in the peptide art and are recommended by the IUPAC-IUBcommission in biochemical nomenclature.

By the term “amino acid residue” is meant an amino acid. In general theabbreviations used herein for designating the naturally occurring aminoacids are based on recommendations of the IUPAC-IUB Commission onBiochemical Nomenclature (see Biochemistry (1972) 11:1726-1732). Forinstance Met, Ile, Leu, Ala and Gly represent “residues” of methionine,isoleucine, leucine, alanine and glycine, respectively. By the residueis meant a radical derived from the corresponding α-amino acid byeliminating the OH portion of the carboxyl group and the H portion ofthe α-amino group.

The term “amino acid side chain” is that part of an amino acid residueexclusive of the backbone, as defined by K. D. Kopple, “Peptides andAmino Acids”, W. A. Benjamin Inc., New York and Amsterdam, 1966, pages 2and 33; examples of such side chains of the common amino acids are—CH₂CH₂SCH₃ (the side chain of methionine), —CH₂(CH₃)—CH₂CH₃ (the sidechain of isoleucine), —CH₂CH(CH₃)₂ (the side chain of leucine) or H-(theside chain of glycine). These side chains are pendant from the backboneCa carbon.

The term “peptide,” as used herein, refers to a sequence of amino acidresidues linked together by peptide bonds or by modified peptide bonds.The term “peptide” is intended to encompass peptide analogs, peptidederivatives, peptidomimetics and peptide variants. The term “peptide” isunderstood to include peptides of any length. Peptide sequences set outherein are written according to the generally accepted conventionwhereby the N-terminal amino acid is on the left, and the C-terminalamino acid is on the right (e.g., H₂N-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-CO₂H).

Certain compounds of the present disclosure may exist in particulargeometric or stereoisomeric forms. The present disclosure contemplatesall such compounds, including cis- and trans-isomers, R- andS-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the disclosure. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in thisdisclosure. Any representation of a particular isomer is merelyexemplary (e.g., the exemplification of a trans-isomer, also encompassesa cis-isomer).

If, for instance, a particular enantiomer of a compound of the presentdisclosure is desired, it may be prepared by asymmetric synthesis or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomer. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomer.

The term “substituted”, as used herein, means that any one or morehydrogen atoms on the designated atom is replaced with a selection fromthe indicated groups, provided that the designated atom's normal valencyis not exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogen atoms on the atomare replaced. Keto substituents are not present on aromatic moieties.Ring double bonds, as used herein, are double bonds that are formedbetween two adjacent ring atoms (e.g., C═C, C═N or N═N). “Stablecompound” and “stable structure” are meant to indicate a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom in thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchformula. Combinations of substituents and/or variables are permissible,but only if such combinations result in stable compounds.

When any variable (e.g., R₁) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R₁ moieties,then the group may optionally be substituted with up to two R₁ moietiesand R₁ at each occurrence is selected independently from the definitionof R₁. Also, combinations of substituents and/or variables arepermissible, but only if such combinations result in stable compounds.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent disclosure includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like. In addition, a crystal polymorphism may bepresent for the compounds represented by the formula. It is noted thatany crystal form, crystal form mixture, or anhydride or hydrate thereofis included in the scope of the present disclosure. Furthermore,so-called metabolite which is produced by degradation of the presentcompound in vivo is included in the scope of the present disclosure.

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

A carbon atom bonded to four nonidentical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisdisclosure include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose.

Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim,amide-imidic acid tautomerism in heterocyclic rings (e.g., innucleobases such as guanine, thymine and cytosine), amine-enamine andenamine-enamine.

It is to be understood that the compounds of the present disclosure maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present disclosure, and the naming ofthe compounds does not exclude any tautomer form.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or a salt or solvate thereof)can crystallize in different crystal packing arrangements, all of whichhave the same elemental composition. Different crystal forms usuallyhave different X-ray diffraction patterns, infrared spectral, meltingpoints, density hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

Additionally, the compounds of the present disclosure, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules. Nonlimitingexamples of hydrates include monohydrates, dihydrates, etc. Nonlimitingexamples of solvates include ethanol solvates, acetone solvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate; and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar or comparable in function and appearance, butnot in structure or origin to the reference compound.

As defined herein, the term “derivative” refers to compounds that have acommon core structure, and are substituted with various groups asdescribed herein.

The term “bioisostere” refers to a compound resulting from the exchangeof an atom or of a group of atoms with another, broadly similar, atom orgroup of atoms. The objective of a bioisosteric replacement is to createa new compound with similar biological properties to the parentcompound. The bioisosteric replacement may be physicochemically ortopologically based. Examples of carboxylic acid bioisosteres include,but are not limited to, acyl sulfonimides, tetrazoles, sulfonates andphosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176,1996.

The present disclosure is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

The synthetic processes of the disclosure can tolerate a wide variety offunctional groups; therefore various substituted starting materials canbe used. The processes generally provide the desired final compound ator near the end of the overall process, although it may be desirable incertain instances to further convert the compound to a pharmaceuticallyacceptable salt, ester or prodrug thereof

Compounds of the present disclosure can be prepared in a variety of waysusing commercially available starting materials, compounds known in theliterature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentdisclosure.

In particular, the compounds of the present disclosure, and theirsynthesis, are further described in PCT Publication Nos. WO 2011/150022and WO 2011/150088 and U.S. Pat. Nos. 9,173,956, 9,320,805, and9,433,600. Each of these publications is incorporated by reference intheir entireties for all purposes.

The present disclosure also provides pharmaceutical compositionscomprising a compound of the present disclosure, or pharmaceuticallyacceptable salts, solvates, diastereomers, and polymorphs thereof, and apharmaceutically acceptable carrier or excipient.

A “pharmaceutical composition” is a formulation containing the compoundsof the present disclosure in a form suitable for administration to asubject. In one aspect, the pharmaceutical composition is in bulk or inunit dosage form. The unit dosage form is any of a variety of forms,including, for example, a capsule, an IV bag, a tablet, a single pump onan aerosol inhaler or a vial. The quantity of active ingredient (e.g., aformulation of the disclosed compound or salt, hydrate, solvate orisomer thereof) in a unit dose of composition is an effective amount andis varied according to the particular treatment involved. One skilled inthe art will appreciate that it is sometimes necessary to make routinevariations to the dosage depending on the age and condition of thepatient. The dosage will also depend on the route of administration. Avariety of routes are contemplated, including oral, pulmonary, rectal,parenteral, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal, inhalational, buccal, sublingual, intrapleural,intrathecal, intranasal, and the like. Dosage forms for the topical ortransdermal administration of a compound of this disclosure includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. In one aspect, the active compound is mixed understerile conditions with a pharmaceutically acceptable carrier, and withany preservatives, buffers or propellants that are required.

As used herein, “pharmaceutically acceptable excipient” or“pharmaceutically acceptable carrier” is intended to include any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like,compatible with pharmaceutical administration. Suitable carriers aredescribed in the most recent edition of Remington's PharmaceuticalSciences, a standard reference text in the field. Preferred examples ofsuch carriers or diluents include, but are not limited to, water,saline, ringer's solutions, dextrose solution, and 5% human serumalbumin.

Pharmaceutically acceptable carriers include solid carriers such aslactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,magnesium stearate, stearic acid and the like. Exemplary liquid carriersinclude syrup, peanut oil, olive oil, water and the like. Similarly, thecarrier or diluent may include time-delay material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or with awax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate orthe like. Other fillers, excipients, flavorants, and other additivessuch as are known in the art may also be included in a pharmaceuticalcomposition according to this disclosure. Liposomes and non-aqueousvehicles such as fixed oils may also be used. The use of such media andagents for pharmaceutically active substances is well known in the art.Except insofar as any conventional media or agent is incompatible withthe active compound, use thereof in the compositions is contemplated.Supplementary active compounds can also be incorporated into thecompositions. In certain aspects, the pharmaceutical compositioncomprises DMSO.

The term “pharmaceutically acceptable salts” refers to the relativelynon-toxic, inorganic and organic acid addition salts of the compound(s).These salts can be prepared in situ during the final isolation andpurification of the compound(s), or by separately reacting a purifiedcompound(s) in its free base form with a suitable organic or inorganicacid, and isolating the salt thus formed. Representative salts includethe hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate,acetate, valerate, oleate, palmitate, stearate, laurate, benzoate,lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, andlaurylsulphonate salts, and the like. Representative alkali or alkalineearth salts include the lithium, sodium, potassium, calcium, magnesium,and aluminum salts, and the like. Representative organic amines usefulfor the formation of base addition salts include ethylamine,diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine,and the like (See, for example, Berge et al. (1977) “PharmaceuticalSalts”, J. Pharm. Sci. 66:1-19)

The phrase “pharmaceutically acceptable” is employed herein to refer tothose ligands, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals, substantiallynon-pyrogenic, without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

As used herein, the term “metabolite” means a product of metabolism ofthe compound of present disclosure, or pharmaceutically acceptablesalts, solvates, diastereomers, and polymorphs thereof, that exhibits asimilar activity in vivo to the compound of present disclosure, orpharmaceutically acceptable salts, solvates, diastereomers, andpolymorphs thereof

As used herein, the term “prodrug” means the compound of presentdisclosure, or pharmaceutically acceptable salts, solvates,diastereomers, and polymorphs thereof covalently linked to one or morepro-moieties, such as an amino acid moiety or other water solubilizingmoiety. The compound of present disclosure, or pharmaceuticallyacceptable salts, solvates, diastereomers, and polymorphs thereof may bereleased from the pro-moiety via hydrolytic, oxidative, and/or enzymaticrelease mechanisms. In an aspect, a prodrug composition of the presentdisclosure exhibits the added benefit of increased aqueous solubility,improved stability, and improved pharmacokinetic profiles. Thepro-moiety may be selected to obtain desired prodrug characteristics.For example, the pro-moiety, e.g., an amino acid moiety or other watersolubilizing moiety such as phosphate within R4, may be selected basedon solubility, stability, bioavailability, and/or in vivo delivery oruptake. Examples of prodrugs include, but are not limited to, esters(e.g., acetate, dialkylaminoacetates, formates, phosphates, sulfates andbenzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl)of hydroxy functional groups, esters (e.g., ethyl esters,morpholinoethanol esters) of carboxyl functional groups, N-acylderivatives (e.g., N-acetyl) N-Mannich bases, Schiff bases andenaminones of amino functional groups, oximes, acetals, ketals and enolesters of ketone and aldehyde functional groups in compounds of thedisclosure, and the like, See Bundegaard, H., Design of Prodrugs, p1-92, Elesevier, New York-Oxford (1985).

The compounds of the present disclosure, or pharmaceutically acceptablesalts, esters, solvates, diastereomers, polymorphs, or pro-drugs thereof(or pharmaceutical compositions thereof) can be administered by anymeans known in the art. For example, the compounds or compositions ofthe present disclosure are administered orally, nasally, transdermally,topically, pulmonary, inhalationally, buccally, sublingually,intraperintoneally, subcutaneously, intramuscularly, intravenously,rectally, intrapleurally, intrathecally and parenterally. Administrationcan be systemic, e.g., intravenous administration, or localized. Incertain aspects, the route of administration may be intravenous,intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal,intrapleural, intrauterine, rectal, vaginal, topical, and the like. Incertain aspects, the compound is administered subcutaneously.

A pharmaceutical composition of the disclosure is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical), andtransmucosal administration. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfate; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates, and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the disclosure can beadministered to a subject in many of the well-known methods currentlyused for chemotherapeutic treatment. For example, for treatment ofcancers, a compound of the disclosure may be injected directly intotumors, injected into the blood stream or body cavities, injectedsubcutaneously, or taken orally or applied through the skin withpatches. The dose chosen should be sufficient to constitute effectivetreatment but not as high as to cause unacceptable side effects. Thestate of the disease condition (e.g., cancer, precancer, and the like)and the health of the patient should preferably be closely monitoredduring and for a reasonable period after treatment.

In one aspect, the compounds of the present disclosure, orpharmaceutically acceptable salts, esters, solvates, diastereomers,polymorphs, or pro-drugs thereof, are administered in a suitable dosageform or formulation prepared by combining a therapeutically effectiveamount (e.g., an efficacious level sufficient to achieve the desiredtherapeutic effect) of the compounds of the present disclosure, orpharmaceutically acceptable salts, esters, solvates, diastereomers,polymorphs, or pro-drugs thereof (as an active ingredient) with standardpharmaceutical carriers or diluents according to conventional procedures(i.e., by producing a pharmaceutical composition of the disclosure).These procedures may involve mixing, granulating, and compressing ordissolving the ingredients as appropriate to attain the desiredpreparation.

Parenteral dosage forms may be prepared by any means known in the art.For example, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents.

Oral dosage forms, such as capsules, tablets, pills, powders, andgranules, may be prepared using any suitable process known to the art.For example, the compounds of the present disclosure may be mixed withenteric materials and compressed into tablets. Alternatively,formulations of the disclosure are incorporated into chewable tablets,crushable tablets, tablets that dissolve rapidly within the mouth, ormouth wash.

For pulmonary (e.g., intrabronchial) administration, the compounds ofthe present disclosure can be formulated with conventional excipients toprepare an inhalable composition in the form of a fine powder oratomizable liquid. For ocular administration, the compounds of thepresent disclosure can be formulated with conventional excipients, forexample, in the form of eye drops or an ocular implant. Among excipientsuseful in eye drops are viscosifying or gelling agents, to minimize lossby lacrimation through improved retention in the eye.

Liquid dosage forms for oral or other administration include, but arenot limited to, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeagent(s), the liquid dosage forms may contain inert diluents commonlyused in the art such as, for example, water or other solvents,solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor, andsesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Besides inertdiluents, the ocular, oral, or other systemically-delivered compositionscan also include adjuvants such as wetting agents, and emulsifying andsuspending agents.

Commercially available nebulizers for liquid formulations, including jetnebulizers and ultrasonic nebulizers are useful for administration.Liquid formulations can be directly nebulized and lyophilized powder canbe nebulized after reconstitution. Alternatively, the compounds of thepresent disclosure can be aerosolized using a fluorocarbon formulationand a metered dose inhaler, or inhaled as a lyophilized and milledpowder.

Dosage forms for topical or transdermal administration of an inventivepharmaceutical composition may include ointments, pastes, creams,lotions, gels, powders, solutions, sprays, inhalants, or patches. Theactive agent is admixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives or buffers as may berequired. For example, cutaneous routes of administration are achievedwith aqueous drops, a mist, an emulsion, or a cream.

Transdermal patches may have the added advantage of providing controlleddelivery of the active ingredients to the body. Such dosage forms can bemade by dissolving or dispensing the compound in the proper medium.Absorption enhancers can also be used to increase the flux of thecompound across the skin. The rate can be controlled by either providinga rate controlling membrane or by dispersing the compound in a polymermatrix or gel.

Compositions for rectal or vaginal administration may be suppositorieswhich can be prepared by mixing the compounds of the present disclosurewith suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active agent(s).Alternatively, contemplated formulations can be administered by releasefrom a lumen of an endoscope after the endoscope has been inserted intoa rectum of a subject.

One skilled in the art may refer to general reference texts for detaileddescriptions of known techniques discussed herein or equivalenttechniques. These texts include Ausubel et al., Current Protocols inMolecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al.,Molecular Cloning, A Laboratory Manual (3d ed.), Cold Spring HarborPress, Cold Spring Harbor, N.Y. (2000); Coligan et al., CurrentProtocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., CurrentProtocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., ThePharmacological Basis of Therapeutics (1975), Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., 18th edition (1990). Thesetexts can, of course, also be referred to in making or using an aspectof the disclosure.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present disclosure areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentdisclosure. The examples do not limit the claimed disclosure. Based onthe present disclosure the skilled artisan can identify and employ othercomponents and methodology useful for practicing the present disclosure.

EXAMPLES

Examples are provided below to further illustrate different features ofthe present disclosure. The examples also illustrate useful methodologyfor practicing the disclosure. These examples do not limit the claimeddisclosure.

Example 1 In Vivo Testing B16F10 Melanoma/DIO Mice—Body Weight, TumorGrowth, Adipose Tissue Mass and White Blood Cell Count

An in vivo study was undertaken to establish a syngeneic mouse model todemonstrate that diet-induced obesity accelerates tumor growth. Thestudy was to demonstrate the efficacy of compounds of the disclosure inthis obesity-fueled, metabolically-driven, tumor model. In particular todemonstrate efficacy against tumors in obese animals and demonstrate aneffect in corresponding lean animals. The study would compare weightchanges in both obese and lean animal groups; measure biologic changesin hematology parameters; and compare conjugate molecules of the presentdisclosure against related small molecules for efficacy.

C57BL/6 male mice were ad libitum fed TD.06414 a high fat diet (HFD)composed of 60% Kcal from fat (DIO) for 12-14 weeks, until average bodyweight of the obese mice was >40 g. Age-matched C57B1/6 male mice weremaintained on a normal rodent diet (10% fat, low-fat diet, LFD) for12-14 weeks. The study was initiated by injecting 2×10⁵ B16F10 melanomacells into the flank of both lean and obese animals.

The mice were treated with 5% mannitol/water (vehicle control), Compound1 or Compound 4 once tumors had reached >100 mm³. Treatment was viasubcutaneous, intra-scapular injection at 5 ml/kg every four days(compound 1) or every 2 days (compound 4) over a 17 day period at thedoses and on the schedule shown in Table 2.

TABLE 2 Treatment Dose (mg/kg) N/group Dose Route/frequency DIO VehicleMannitol/water 10 SC/Q4D (HFD) Control days 1, 5, 9, 13, 17 Compound 1 810 SC/Q4D days 1, 5, 9, 13, 17 Compound 1 24  10 SC/Q4D days 1, 5, 9,13, 17 Compound 4 2 10 SC/Q2D days 1, 3, 5, 7, 9, 11, 13, 15, 17 LeanVehicle Mannitol/water 10 SC/Q4D (LFD) Control days 1, 5, 9, 13, 17Compound 1 8 10 SC/Q4D days 1, 5, 9, 13, 17 Compound 1 24  10 SC/Q4Ddays 1, 5, 9, 13, 17 Compound 4 2 10 SC/Q2D days 1, 3, 5, 7, 9, 11, 13,15, 17

Compound 4 is CKD-732 (also known as beloranib and ZGN-433). Compound 4was previously shown to be efficacious in eliciting weight loss in DIOmice when dosed at 1 mg/kg (Hughes T E., et al “ZGN-201 (ZGN), amethionine aminopeptidase 2 (MetAP2) inhibitor, durably eliminatesexcess body fat in obese mice through regulation of fat metabolism andfood intake.” European Association for the Study of Diabetes; Sep.20-24, 2010; Stockholm, Sweden. Presentation 244.). Compound 4 asreferred to herein is the hemitartrate salt of the following structure:

FIG. 1A shows baseline body weight in obese and lean mice bearing B16F10melanoma. FIG. 1B shows B16F10 melanoma tumor growth in obese and leanmice over time. The data were analyzed using two-way ANOVA with multiplecomparisons, ***p<0.005 and ****p<0.0001. The results of FIG. 1Ademonstrate that the mean body weight of the obese cohorts wassignificantly different from mean body weight of lean cohorts, prior tostudy initiation, and that there were no significant differences in bodyweight within the obese or lean cohorts. The results of FIG. 1Bdemonstrate that tumors grew significantly faster and achieved asignificantly larger size in animals made obese by consuming a high-fatdiet (DIO mice) compared to age-matched animals that consumed a low-fatdiet (lean mice).

FIG. 2A shows B16F10 melanoma tumor growth in lean mice followingtreatment with vehicle or 8 mg/kg or 24 mg/kg of compound 1 of thepresent disclosure. FIG. 2B shows B16F10 melanoma tumor growth in obesemice following treatment with vehicle or 8 mg/kg or 24 mg/kg of compound1 of the present disclosure. The data were analyzed using two-way ANOVAwith multiple comparisons, *p<0.05, **p<0.01, ***p<0.005 and****p<0.0001. The results of FIGS. 2A and 2B demonstrate that compound 1inhibited tumor growth in both lean and obese animals in adose-dependent manner. However, in FIG. 2C the magnitude of inhibitionwas greater in obese animals (58% and 76% reduction of tumor volume inobese mice after 8 and 24 mg/kg of Compound 1, respectively) compared tolean mice (43% and 55% reduction of tumor volume after 8 and 24 mg/kg ofCompound 1, respectively).

FIG. 3A shows body weight in lean mice bearing B16F10 melanomasfollowing treatment with vehicle or 8 mg/kg or 24 mg/kg of compound 1 ofthe present disclosure. FIG. 3B shows body weight in obese mice bearingB16F10 melanomas mice following treatment with vehicle or 8 mg/kg or 24mg/kg of compound 1 of the present disclosure. The data were analyzedusing two-way ANOVA with multiple comparisons, *p<0.05, **p<0.01,***p<0.005 and ****p<0.0001. The results of FIGS. 3A and 3B demonstratethat compound 1 reduced body weight in both lean and obese mice.However, the magnitude of weight loss was greater in obese animals (−19%and −27% change in body weight (relative to baseline) in obese mice inresponse to 8 and 24 mg/kg of Compound 1, respectively) compared to leanmice (−11% and −7% change in body weight (relative to baseline) inresponse to 8 and 24 mg/kg of Compound 1, respectively).

FIG. 4 shows the relationship between body weight and tumor size invehicle- and Compound 1-treated DIO and lean mice. The results of FIG. 4demonstrate that the effect of compound 1 to decrease tumor size relatesto its ability to reduce body weight. This effect was more robust (basedon magnitude of change in both parameters, as well as the greater slopeof the regression line for obese mice) and was more tightly correlatedin obese compared to lean mice (based on p-value from linear regressionanalysis).

FIG. 5 shows the mean (+/−SEM) number of metastatic lung lesions inobese and lean B16F10 melanoma/DIO mice following treatment with vehicleor 8 mg/kg or 24 mg/kg of compound 1 of the present disclosure or 2mg/kg of another MetAP2 inhibitor (Compound 4). The results of FIG. 5demonstrate that obese mice have numerically more metastases to thelungs compared to lean animals (3.6+/−1.4 lesions/mouse versus0.4+/−0.24 lesions/mouse in obese compared to lean mice, respectively;not statistically different). The results also show that compound 1reduced the number of lung metastases in obese mice in a dose-dependentmanner (1.38+/−0.73 lesions/mouse and 0.5+/−0.22 lesions/mouse after 8and 24 mg/kg respectively), although the differences were notstatistically significant. The other MetAP2 inhibitor (Compound 4) had asmall effect on the number of lung metastases in obese mice (2.4+/−0.8lesions/mouse). No differences were seen in lung metastases between thegroups of lean mice (data not shown).

Table 3 shows adipose tissue mass in obese mice bearing B16F10 melanomafollowing treatment with vehicle or 8 mg/kg or 24 mg/kg of compound 1 ofthe present disclosure or another MetAP2 inhibitor (Compound 4) The datawere analyzed using one-way ANOVA with multiple comparisons, *p<0.05,**p<0.01, ***p<0.005 and ****p<0.0001. The results of Table 3demonstrate that obese, tumor-bearing mice have significantly greateradipose tissue mass compared to lean, tumor-bearing animals. They alsoshow that compound 1 reduced body fat in obese animals (the results werestatistically significant only in epididymal adipose tissue). Note thatadipose tissue mass in the control, vehicle-treated animals is 2-5 timeslower than in non-tumor-bearing DIO mice (not shown)

Table 3 also shows adipose tissue mass in lean mice bearing B16F10melanoma following treatment with vehicle or 8 mg/kg or 24 mg/kg ofcompound 1 of the present disclosure or another MetAP2 inhibitor(Compound 4). The data were analyzed using one-way ANOVA with multiplecomparisons, *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001. The resultsof Table 3 demonstrate that none of the adipose tissue depots in leanmice were affected by treatment with compound 1.

TABLE 3 P Value (One-way ANOVA with multiple Treatment Group TissueWeight (g) SEM comparisons) Obese Mice Epididymal Fat Vehicle 0.7790.107 Compound 1 (8 mg/kg) 0.464 0.071 <0.05 Compound 1 (24 mg/kg) 0.3350.053 <0.01 Compound 4 (2 mg/kg) 0.424 0.034 <0.01 Retroperitoneal FatVehicle 0.242 0.045 Compound 1 (8 mg/kg) 0.161 0.022 NS Compound 1 (24mg/kg) 0.103 0.018 NS Compound 4 (2 mg/kg) 0.142 0.019 NS Inguinal FatVehicle 0.713 0.118 Compound 1 (8 mg/kg) 0.596 0.061 NS Compound 1 (24mg/kg) 0.417 0.057 NS Compound 4 (2 mg/kg) 0.416 0.056 <0.05 Lean MiceEpididymal Fat Vehicle 0.134 0.041 Compound 1 (8 mg/kg) 0.133 0.024 NSCompound 1 (24 mg/kg) 0.110 0.024 NS Compound 4 (2 mg/kg) 0.134 0.041<0.01 Retroperitoneal Fat Vehicle 0.056 0.025 Compound 1 (8 mg/kg) 0.0390.012 NS Compound 1 (24 mg/kg) 0.064 0.017 NS Compound 4 (2 mg/kg) 0.0290.017 NS Inguinal Fat Vehicle 0.128 0.029 Compound 1 (8 mg/kg) 0.1290.025 NS Compound 1 (24 mg/kg) 0.212 0.063 NS Compound 4 (2 mg/kg) 0.2080.107 NS

FIG. 6 shows white blood cell count in obese and lean B16F10melanoma/DIO mice following treatment with vehicle or 8 mg/kg or 24mg/kg of compound 1 of the present disclosure or another MetAP2inhibitor (Compound 4). The data were analyzed using one-way ANOVA withmultiple comparisons, *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001.The results of FIG. 6 demonstrate that obese mice exhibit leukocytosis(elevated levels of circulating white blood cells (WBCs)), and thatcompound 1 reduces WBCs. FIG. 6 also demonstrates that obese miceexhibited greater sensitivity to the effect on WBCs since there was asignificant effect in response to 8 mg/kg of compound 1 in obese micebut not in lean mice.

FIG. 7 shows B16F10 melanoma tumor growth in obese and lean micefollowing treatment with vehicle or 2 mg/kg of an un-conjugated smallmolecule MetAP2 inhibitor (compound 4). The results of FIG. 7demonstrate that compound 4 significantly inhibited the growth of tumorsin obese mice (by 28%), although the magnitude of the effect was smallerthan what was observed with compound 1 (57% reduction at 8 mg/kg). Incontrast to what was observed with compound 1, compound 4 had no effecton tumor growth in lean mice.

To directly compare the amount of active MetAP2 inhibitor delivered byCompound 1 at 8 mg/kg versus Compound 4 at 2 mg/kg one must account forthe quantity of active in Compound 1, which is approximately 20% byweight, or 1.6 mg/kg of active delivered in a dose of 8 mg/kg.Additionally the dosing frequency of Compound 1 was every four days;half as often as Compound 4. Therefore the dose of active MetAP2inhibitor delivered to the mice from Compound 1 was approximately 2.5times lower than the active MetAP2 inhibitor delivered from the Compound4 (on a mg/kg basis for each dose). However to compare the total amountof active MetAP2 inhibitor delivered over the period of the study (17days) the difference in dosing frequency must also be taken into account(Compound 4 was dosed every two days versus every 4 days for Compound1). In total, nine doses of Compound 4 were given versus 5 doses ofCompound 1, which means that 2.25 times more active MetAP2 inhibitor wasdelivered with Compound 4 versus Compound 1. Despite the greater amountof active MetAP2 delivered with Compound 4, its efficacy was lower thanCompound 1, highlighting the superior and unexpected benefits providedby the compounds of the instant disclosure.

FIG. 8 shows body weight of tumor-bearing obese and lean mice followingtreatment with vehicle or 2 mg/kg of another small molecule MetAP2inhibitor (compound 4). The results of FIG. 8 demonstrate that compound4 significantly decreased body weight in obese mice (−7.9% after 2mg/kg), although the magnitude of the effect was smaller than what wasobserved with Compound 1 (−18.9% after 8 mg/kg) despite the greateramount of compound 4 delivered over the course of the study (asdiscussed above). In contrast to what was observed with compound 1,compound 4 had no effect on body weight in lean mice.

Example 2 In Vivo Testing DIO Mice—Leptin and Adiponectin

Leptin is an adipocyte-derived hormone that was discovered based uponits ability to inhibit caloric intake by signaling through receptorslocated on neurons within the hypothalamus of the central nervous system(CNS). Genetic deletion of leptin in mice and humans causes severeobesity, which is reversed following exogenous delivery of recombinantleptin. The circulating levels of leptin are positively correlated withthe mass of adipose tissue in the host, and elevated levels of leptinobserved in obese animals and humans. Unlike normal weight animals andhumans, obese animals and humans do not sense their endogenouslyelevated levels of leptin and are resistant to its anorectic,anti-obesity effects. Given the prolonged and persistent time course ofobesity development, peripheral tissues and organs are exposed toelevated levels of leptin over many years. Since leptin is nowrecognized to regulate a number of biological processes outside of theCNS (e.g., immune function, angiogenesis, vascular endothelialhomeostasis, stem cell renewal) adverse consequences of exposure toabnormally high levels of leptin are now being recognized. In particularleptin has been shown to activate survival pathways in cancer stem cells(e.g., Oct4) and thus is a likely contributor to recurrence of cancer(Feldman et al, PNAS, 2012, 109(3), 829-834). Additionally, preclinicalmodels of tumor development have shown that leptin, derived from humanadipose stromal cells can directly increase cancer cell proliferation,as well as contribute to metastatic disease. Importantly the effect ofASC-derived leptin is significantly greater when the ASCs are isolatedfrom obese human donors, as opposed to lean human donors (Strong et al.Breast Can. Res., 2015, 17:112). Therefore leptin has been suggested asa component of the mechanistic link between obesity and cancer (Park etal, Nat Rev Endocrinol. 2014, 10(8): 455-465).

Another endpoint of interest in both metabolic disease and now (fromboth a mechanistic as well as prognostic standpoint) in cancer, is theadipocyte-derived hormone adiponectin. This protein is released fromadipocytes into the circulation where it acts on liver and muscle tissueto elicit beneficial responses by enhancing the action of insulin. Morerecently adiponectin has been shown to directly regulate pathways thatcontrol malignant potential (cell proliferation, adhesion, invasion andcolony formation), regulate metabolic (AMPK/S6), inflammatory(STAT3/VEGF) and cell cycle (p21/p27/p53/cyclins) in both mouse MCA38and human HT29, HCT116 and LoVo colon cancer cell lines in aLKB1-dependent manner, suggesting that adiponectin may be protective incolorectal cancer (Moon et al, Gut, 2013, 2(4):561-70). A recentclinical study showed that adiponectin may be protective against therecurrence of cancer since increased levels positively correlated withdisease-free survival in breast cancer (Duggan et al, J Clin Oncol,2011, 29(1):32-9). Given the potential role of the two hormones leptinand adiponectin in metabolic disease and cancer, plasma levels of leptinand adiponectin were measured (using an ELISA) in samples obtained fromin vivo studies of obese animals after dosing compound 1 in obese andlean mice bearing syngeneic B16F10 melanomas, or obese mice withouttumors.

Male C57BL/6 mice were ad libitum fed TD.06414 a high fat diet (HFD)composed of 60% Kcal from fat (DIO) for 16 weeks, until average bodyweight was >40 g.

The mice were treated with 5% mannitol in water (vehicle control) andCompound 1. Treatment was via subcutaneous injection at 5 ml/kg everyfour days (q4d) with compound 1 injected at either 2.0 mg/kg or 6.0mg/kg.

FIG. 9A shows the levels of serum leptin in obese DIO mice followingtreatment with vehicle or 2 mg/kg or 6 mg/kg of compound 1 of thepresent disclosure. FIG. 9B shows serum adiponectin in obese DIO micefollowing treatment with vehicle or 2 mg/kg or 6 mg/kg of compound 1 ofthe present disclosure. The data were analyzed using one-way ANOVA withmultiple comparisons, *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001.The results in FIG. 9A and FIG. 9B demonstrate that compound 1 reducesserum leptin levels and increases serum adiponectin at each dose tested.In particular, compound 1 has a significant effect at decreasing serumleptin levels.

FIG. 9C shows the ratio of serum leptin:adiponectin from obese DIO micefollowing treatment with vehicle or 2 mg/kg or 6 mg/kg of compound 1 ofthe present disclosure. The data were analyzed using one-way ANOVA withmultiple comparisons, *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001.The results in FIG. 9C show a reduction in the leptin:adiponectin ratioat each dose tested. In particular, compound 1 has a significant effectat decreasing leptin:adiponectin serum levels at the 6 mg/kg dose.

FIG. 9D shows the levels of serum adiponectin in lean mice bearingB16F10 melanomas following treatment with vehicle, 8 mg/kg or 24 mg/kgof compound 1 or 2 mg/kg of compound 4. FIG. 9E shows the levels ofserum adiponectin in obese DIO mice bearing B16F10 melanoma followingtreatment with vehicle, 8 mg/kg or 24 mg/kg of compound 1 or 2 mg/kg ofcompound 4. The data show a one-way ANOVA with multiple comparisons,*p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001. The results in FIG. 9Dand FIG. 9E demonstrate that compound 1 significantly increases serumadiponectin levels in both lean and obese, tumor-bearing mice. Incontrast, compound 2 had no effect on serum adiponectin levels in eitherlean or obese tumor-bearing mice.

Example 3 In Vivo Testing E0771 Mammary Tumor/DIO Mice—Tumor Growth,Body Weight

Female mice were surgically ovariectomized then fed a high fat diet (60%fat) for 14 weeks, to induce obesity and metabolic dysfunction or alow-fat diet (10% fat). Subsequently mammary gland tumors were inducedby injecting syngeneic E0771 cells into the fourth mammary gland(50,000/mouse). When tumors became palpable, Compound 1 (at 24 mg/kg) orvehicle (5% mannitol/water) were dosed subcutaneously every four daysfor a total of four doses.

FIG. 10A shows tumor growth in lean E0771 Mammary Tumor /DIO micefollowing treatment with vehicle or 24 mg/kg of compound 1 of thepresent disclosure. FIG. 10B shows tumor growth in obese E0771 MammaryTumor /DIO mice following treatment with vehicle or 24 mg/kg of compound1 of the present disclosure. The data were analyzed using two-way ANOVAwith multiple comparisons, *p<0.05, **p<0.01, ***p<0.005 and****p<0.0001. The results of FIGS. 10A and 10B demonstrate that EO771tumors in obese female mice were 71% larger on day 15 than in leanfemale mice. The results also show that compound 1 reduced tumor growthin both lean and obese female mice, with a similar magnitude of effecton tumor size (52% reduction in obese mice compared to 53% reduction inlean mice).

FIG. 11A shows body weight in lean EO771 Mammary Tumor mice followingtreatment with vehicle or 24 mg/kg of compound 1 of the presentdisclosure. FIG. 16B shows body weight change relative to baseline inlean EO771 Mammary Tumor mice following treatment with vehicle or 24mg/kg of compound 1 of the present disclosure. FIG. 11C shows bodyweight in obese EO771 Mammary Tumor mice following treatment withvehicle or 24 mg/kg of compound 1 of the present disclosure. FIG. 1Dshows body weight change in obese EO771 Mammary Tumor mice followingtreatment with vehicle or 24 mg/kg of compound 1 of the presentdisclosure. The data were analyzed using two-way ANOVA with multiplecomparisons, *p<0.05, **p<0.01, ***p<0.005 and ****p<0.0001. The resultsof FIG. 11A-11D demonstrate that compound 1, dosed at 24 mg/kg everyfour days, reduced body weight in both lean and obese female micebearing mammary gland tumors, with a similar magnitude of effect (18%reduction in lean mice and 21% reduction in obese mice, respectively).

Table 4 shows that compound 1 significantly decreased the mass ofadipose tissue (three depots—parametrial, retroperitoneal andinguinal—measured at necropsy) in obese mice, after treatment everyother day for two weeks. Similar effects of Compound 1, though lesssignificant, were observed in lean mice.

TABLE 4 P Value (One-way ANOVA with multiple Treatment Group TissueWeight (g) SEM comparisons) Obese Female Mice Parametrial Fat Vehicle1.845 0.163 Compound 1 (24 mg/kg) 1.175 0.100 <0.005 Retroperitoneal FatVehicle 0.986 0.081 Compound 1 (24 mg/kg) 0.489 0.054 <0.001 InguinalFat Vehicle 2.413 0.205 Compound 1 (24 mg/kg) 1.211 0.085 <0.001 LeanMice Parametrial Fat Vehicle 1.015 0.138 Compound 1 (24 mg/kg) 0.4530.047 <0.01 Retroperitoneal Fat Vehicle 0.393 0.043 Compound 1 (24mg/kg) 0.173 0.035 <0.05 Inguinal Fat Vehicle 0.855 0.162 Compound 1 (24mg/kg) 0.480 0.073 NS

Example 4 Phase 1 Dose Escalation Study of Compound 1 to Assess theSafety and Tolerability in Patients with Advanced Refractory orLate-Stage Solid Tumors—Study Design

The phase 1 clinical trial of compound 1 has several objectives.

The primary objectives are:

-   -   To determine the safety and tolerability of COMPOUND 1 in        patients with advanced refractory or late-stage solid tumors.    -   To determine the maximum tolerated dose (MTD) of COMPOUND 1 in        patients with advanced refractory or late-stage solid tumors.    -   To determine the recommended Phase 2 dose (RP2D) of COMPOUND 1        in patients with advanced refractory or late-stage solid tumors.

The secondary objectives are:

-   -   To evaluate the pharmacokinetic (PK) profile of compound 5, the        active moiety of COMPOUND 1 and metabolites in patients with        advanced refractory or late-stage solid tumors.    -   To document evidence of anti-tumor activity of COMPOUND 1 in        patients with advanced refractory or late-stage solid tumors.

Exploratory objectives include:

-   -   To evaluate the effects of COMPOUND 1 by biomarker analysis, and        by PET scan imaging (where clinically relevant and approved by        the Investigator and Medical Monitor) in patients with advanced        refractory or late-stage solid tumors.    -   To evaluate the pharmacodynamic (PD) effects of COMPOUND 1 by        MetAP2 analysis, and by DCE MRI imaging (where clinically        relevant and approved by the Investigator and Medical Monitor)        in patients with advanced refractory or late-stage solid tumors.    -   To document the effects of COMPOUND 1 on metabolic parameters in        patients with advanced refractory or late-stage solid tumors.    -   To evaluate muscle and fat tissue volumes in the body by MRI or        CT imaging in selected patients.

Study Description

This is a Phase 1 dose escalation study to assess the safety andtolerability of subcutaneously administered COMPOUND 1 in patients withadvanced refractory or late-stage solid tumors. An accelerated titrationdose escalation design will be used with one patient per dose leveluntil that patient has a Grade 2 toxicity deemed by the Investigator aspossibly, probably, or definitely related to study drug in their firstcycle of treatment. A cycle is 28 days, consisting of a total of4-weekly treatments and includes the pre-dose safety testing prior toinitiating the next treatment cycle. Once a Grade 2 toxicity deemed atleast possibly related to study drug is observed in a patient's firstcycle of treatment, the accelerated phase of the study will end and thenon-accelerated phase (3+3 dose escalation design) will begin. A minimumof three evaluable patients will be accrued at the dose that triggeredthe switch to the non-accelerated design and at each subsequent doselevel until a dose limiting toxicity (DLT) is found.

During the accelerated titration dose escalation design phase theSponsor, Medical Monitor, and Safety Review Committee (SRC) may decideto switch to the 3+3 non-accelerated dose escalation phase prior to theobservance of any Grade 2 toxicity deemed at least possibly related tostudy drug in the patient's first cycle of treatment.

In the 3+3 non-accelerated phase, if one of the three patients has a DLT(as defined below), the cohort will be expanded to a maximum of sixpatients. If only one of the six patients has a DLT, dose escalationwill continue. If two patients have a DLT, dose escalation will stop,regardless of the number of patients that have been treated in thiscohort (e.g., if patients 1 and 4 have DLTs then patients 5 and 6 wouldnot be treated). The dose at which two of six patients have a DLT willbe considered at least one dose level above the MTD. The next lower dosewill be fully evaluated by treating a total of six patients. If two ormore patients have DLTs at this lower dose level, de-escalation willcontinue until a dose level is identified at which none or one of sixpatients has a DLT. This dose will be identified as the MTD.

Once the MTD has been determined, up to six more patients, for a totalof up to 12 patients may be treated at this dose level to furthercharacterize treatment emergent adverse events (TEAEs).

Patients who experience a Grade 3 or greater toxicity that is deemed bythe Investigator to be possibly, probably, or definitely related to theadministration of COMPOUND 1, can have their next dose withheld for upto 14 days (the day that the dose is due being considered Day 1 of thedose delay), and when the patient's toxicity has returned to a Grade 1or to the patient's pre-event baseline, the treatment can be resumed atthe same dose level. Patients that have their dose withheld longer than14 days, will be discontinued from the study. Dose delays for up to twoweeks from the scheduled Day 1 start of treatment may be considered forthe patient's clinical concerns, which may be deemed not related to thestudy drug, upon agreement between the Investigator, Medical Monitor andthe patient.

During the study, the SRC may decide if additional dose groups should beopened. New dose groups either above or below the highest dose used canbe added with the approval of the Investigator(s), Medical Monitor andSRC.

Intra-patient dose escalation to the next higher cohort will beconsidered for those patients who have not demonstrated a Grade 2toxicity deemed at least possibly related to study drug, in their firstcycle and have successfully completed their Tumor Burden Assessmentafter Cycle 2. This type of dose escalation will only be allowed once apatient in the next higher dose cohort has successfully completed theirCycle 1 safety assessment by not demonstrating a Grade 2 toxicity eventthat is deemed at least possibly related to study drug. The decision todose escalate will be made in a discussion between the Investigator,Medical Monitor and Sponsor, taking in account the patient's permission.If a patient escalates to the next higher dose level at Cycle 4, 5, or 7and beyond, additional plasma PK samples will be collected according toa defined schedule.

Patients will be allowed to continue treatment:

-   -   if there is a clinical response, or    -   if they have stable disease as assessed on imaging studies        following C2, C4, C6 and every three cycles subsequently, or    -   if the Investigator and Medical Monitor agree that the patient        is receiving benefit from the treatment.

Each patient will be dosed once weekly for 4 weeks (days 1, 8, 15, and22) and includes a safety follow-up prior to initiation of the nexttreatment cycle. Patients will go through 2 cycles prior to diseaseassessment by RECIST 1.1 criteria. Below are the following dose levelsthat will be used:

Dose cohort Proposed dose level (mg/m²) 1 1.7 2 3.4 3 6.0 4 8.5 511.9^(a) 6 15.3 7 20.4^(b) 8 27.0 9 36.0 10  49.0 11+ Additional cohorts^(a)NOAEL in dog was 0.4 ng/ml COMPOUND 5 (Cmax)/20.7 h * ng/ml (AUC)after a dose of 0.5 mg/kg (10 mg/m²) COMPOUND 1 ^(b)NOAEL in rat was 1.5ng/ml COMPOUND 5 (Cmax)/23.3 h * ng/ml (AUC) after a dose of 3 mg/kg (18mg/m²) COMPOUND 1

The Common Terminology Criteria for Adverse Events (CTCAE) v4.02 will beused to determine toxicity.

A DLT is defined as any of the following adverse events that areclinically significant and are deemed by the Investigator to bepossibly, probably, or definitely related to the administration ofCOMPOUND 1 that persist(s) despite maximal medical support:

-   -   any Grade 3 or greater non-hematological toxicity; lasting        seven (7) days, or    -   any Grade 3 or greater nausea, diarrhea, and/or vomiting lasting        three (3) days, provided the patient received maximal medical        intervention and/or prophylactic anti-emetic therapy; or    -   any Grade 3 or greater hematologic toxicity; lasting three (3)        days, or    -   any Grade 3 or greater febrile neutropenia.

Study Population: Approximately 30 patients

Study Drug Administration: COMPOUND 1 will be administered bysubcutaneous injection on days, 1, 8, 15, and 22 of each cycle, andincludes a safety follow-up prior to initiation of the next treatmentcycle.

Inclusion Criteria:

The patient has the ability to provide written, informed consent, tounderstand the requirements of the study, and agree to abide by therequirements of the study.

Male or female ≧21 to ≦85 years of age.

Patients with histologically or cytologically confirmed advanced,refractory, late-stage solid tumors who have progressed on standardtherapy or for whom no effective anti-cancer therapy is available.

Patients with at least one site of radiographically measurable diseaseof ≧1 cm in the largest dimension by traditional computerized tomography(CT) scanning technique (per RECIST 1.1 criteria); or if, in theInvestigator's opinion, evaluable disease can be reliably andconsistently followed, the patient may be eligible upon approval by theMedical Monitor.

Eastern Cooperative Oncology Group (ECOG) status ≦1.

Life expectancy ≧3 months.

Women of childbearing potential must not be breastfeeding or lactatingand must have a negative serum pregnancy test within 72 hours ofstarting the study. If the female partner is not menopausal or is notsurgically sterile, then women and men study patients must be willing touse double barrier birth control methods such as condom or occlusive cap(e.g., diaphragm or cervical/vault caps) plus spermicidal agent (e.g.,foam, gel, film, cream, suppository) throughout the duration of theirparticipation in the study, including a 90 day period after their lasttreatment.

Laboratory data as specified below:

-   -   Hematology: ANC>1500 cells/mm³, platelet count>100,000 cells/mm³        and hemoglobin>9 g/dL.    -   Urinalysis: No clinically significant abnormalities.    -   Coagulation: INR and PTT within normal limits.    -   HIV-positive patients are eligible provided the following        criteria are met: CD4 count ≧100/mm³, undetectable viral load        within the past 3 months, receiving a stable antiretroviral        regimen for ≧4 weeks before study entry.

Patients eligible for imaging study scans must be able to lie flat forup to 45 minutes.

Exclusion Criteria

Patients that have undergone organ transplant surgery.

Patients with known primary brain malignancy, brain metastases or activeCNS pathology.

Patients with known history of Hepatitis A, B, or C that are on activeanti-viral therapy.

Patients on anticoagulation medication; however, standard dose ASA,anti-platelet agents, are allowed as approved in advance by MedicalMonitor.

Patients with a history of gastric bypass surgery or banding procedure.

Patients requiring insulin for control of diabetes. Subjects takinginsulin secretagogues that act in a non-glucose dependentmanner—sulfonylureas such as glyburide and any in this class.

Patients on greater than physiological replacement equivalentcorticosteroids; e.g., prednisone 5 mg, dexamethasone 0.75 mg,hydrocortisone 20 mg, betamethasone 0.6 mg, methylprednisolone 4 mg,cortisone 25 mg, etc., per day. Nasal, inhaled, and topicalcorticosteroids are permitted.

Patients with uncontrolled or refractory hypertension: systolic>180 ordiastolic>110, or hypotension: systolic<90 or diastolic<50 despitemedical treatment.

Patients for whom the resting 12-lead electrocardiogram obtained duringscreening shows QTc (Bazett's correction)≧470 ms or that have congenitalprolonged QT syndrome. Isolated right bundle branch block (RBBB) andincomplete right bundle branch block (IRBBB) and left anterior hemiblock(LAH) are acceptable. Any uncontrolled cardiac arrhythmia (patients withrate-controlled atrial fibrillation are not excluded unless on chronicanti-coagulation as per Exclusion Criterion #4).

Renal: serum creatinine>1.5X upper limit of normal (ULN), or calculatedcreatinine clearance<50 mL/min/1.73 m² for patients with creatininelevels above institutional normal.

Hepatic: Total bilirubin≧1.5X ULN; alanine aminotransferase (ALT) oraspartate aminotransferase (AST)≧2.5X ULN. For patients with known livermetastases or liver neoplasms, then ALT or AST≦5.0X ULN is allowed.

Participation in any other trial of an investigational agent within 30days prior to first dose of study drug.

Previous Therapies:

-   -   treatment with the following medications≦4 weeks or 5        half-lives, whichever is shorter, prior to first dose of study        drug:        -   any treatment with cytotoxic or cytostatic chemotherapy,            monoclonal antibody therapy, radiation therapy, molecular            targeted therapy, hormonal agents, TKIs (tyrosine kinase            inhibitors), angiogenesis and VEGF inhibitors.    -   major surgery≦4 weeks prior to study first dose of study drug.    -   any radio-immunotherapy≦12 weeks prior to first dose of study        drug.

Any other concurrent condition or social situation, which in the opinionof the Investigator, would preclude participation in this study orinterfere with the patient's study compliance.

Any serious medical condition, laboratory abnormality, or psychiatricillness that would prevent the patient from following study procedure orplaces the patient at unacceptable risk if s/he were to participate inthe study or confounds the ability to interpret data from the study.

Patients with a known history of hypersensitivity to any of the testmaterials or related compounds.

Patients requiring chronic, concomitant treatment of strong cytochromeP450, family 3, subfamily A, polypeptide 4 (CYP3A4/5) inducers (e.g.,dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,rifapentine, phenobarbital, and St. John's Wort) given that thebiologically active small molecule moiety of COMPOUND 1, COMPOUND 5, isa CYP3A 4 & 5 substrate.

Patients who have had radiotherapy≦4 weeks prior to starting study drug,or ≦2 weeks prior to starting study drug in the case of localizedradiotherapy (e.g. for analgesic purpose or for lytic lesions at risk offracture), or who have not recovered from radiotherapy toxicities.

Prior use of prescription or non-prescription orexigenics (appetitestimulants), (i.e., megestrol acetate, mirtazapine, dronabinol, anabolicsteroids) within 2 months of first dose of study drug.

Study Assessments

Below is a summary of the requirements and tests needed prior toenrollment and that will be performed during a patient's participationin this Phase 1 study.

Screening Period (up to 14 days prior to Day 1)

-   -   Signed informed consent    -   Medical history    -   Physical examination (all body systems); may defer rectal and        genital exam if not clinically indicated    -   Height and weight    -   ECOG Performance Status    -   Vital signs (temperature, blood pressure, pulse and respiratory        rate)    -   Concomitant medication assessment    -   12-lead electrocardiogram (triplicate)    -   Serum Pregnancy test (for nonsterile women of childbearing        potential)    -   Hematology    -   Clinical chemistry, coagulation, lipid, and urinalysis        (microscopic examination if positive on dipstick)    -   Assessment of tumor burden by radiologic evaluations using        RECIST 1.1 criteria (CT scans can be used if captured no more        than 30 Days prior to Treatment Day 1)    -   PET and DCE MRI Scan as clinically indicated, and approved by        the Investigator and Medical Monitor    -   MRI or CT scan for selected patients approved by the        Investigator and Medical Monitor for body composition analysis,        see Imaging Manual    -   Record any available clinically accepted assay results for        protein biomarkers relevant to the patient's specific tumor type        (e.g., PSA, CA-125, AFP, CEA, beta-hCG, CA19-9, etc.)

Treatment Period (Pre-dose testing with the exception of PK, PD,biomarkers and retains can be performed within 72 hours prior totreatment)

-   -   Medical history    -   Weight (every treatment day pre-dose for study drug        calculation—weight from the previous visit may be used for study        drug dosing calculations)    -   Questions on eating habits, diet, and physical activity    -   ECOG Performance Status (Pre-dose Day 1 of each cycle)    -   Vital signs (temperature, blood pressure, pulse and respiratory        rate)    -   Concomitant medication assessment    -   12-lead electrocardiogram (triplicate).    -   Local tolerance of subcutaneous treatment injection site(s)    -   Serum pregnancy test for female patients with childbearing        potential (Pre-dose Day 1)    -   Hematology    -   Clinical chemistry, coagulation, lipid, and urinalysis        (microscopic examination if positive on dipstick)    -   Blood sample collection for PK and PD analysis    -   Blood sample collection for exploratory biomarkers and retains    -   PET and DCE MRI scans as clinically indicated, and approved by        the Investigator and Medical Monitor, see Imaging Manual    -   MRI or CT scan for selected patients approved by the        Investigator and Medical Monitor for body composition analysis,        see Imaging Manual    -   Tumor burden assessment using RECIST 1.1 conducted every other        cycle (i.e. at end of Cycles 2, 4, and 6). After Cycle 6 is        completed, tumor burden assessment will be performed every 3        Cycles. If a stable or positive response is noted, a follow-up        (4 weeks) confirmatory radiographic assessment will be performed    -   Record any available clinically accepted assay results for        protein biomarkers relevant to the patient's specific tumor type        (e.g., PSA, CA-125, AFP, CEA, beta-hCG, CA19-9, etc.)    -   Review of adverse events (includes symptom review)

End-of-Treatment (EOT) Assessments (The EOT visit will be scheduled assoon as possible after the investigator decides that the study drugtreatment is no longer an option or after the patient withdraws from thestudy)

-   -   Weight    -   Questions on diet, eating habits, and physical activity    -   ECOG Performance Status    -   Vital signs (temperature, blood pressure, pulse and respiratory        rate)    -   Concomitant medication assessment    -   12-lead electrocardiogram (triplicate)    -   Local tolerance of the subcutaneous treatment injection site(s)    -   Hematology    -   Clinical chemistry, coagulation, lipid, and urinalysis        (microscopic examination)    -   Blood sample collection for PK and PD analysis    -   Blood sample collection for exploratory biomarkers and retains    -   Tumor burden assessment using RECIST 1.1 will be done    -   Record any available clinically accepted assay results for        protein biomarkers relevant to the patient's specific tumor type        (e.g., PSA, CA-125, AFP, CEA, beta-hCG, CA19-9, etc.)    -   Review of adverse events (includes symptom review)

End-of-Study (EOS) Assessments (The EOS is 30-days after the EOT (±3days) visit)

-   -   Physical exam    -   Height and Weight    -   Questions on diet, eating habits, and physical activity    -   ECOG Performance Status    -   Vital signs (temperature, blood pressure, pulse and respiratory        rate)    -   Concomitant medication assessment    -   12-lead electrocardiogram (triplicate)    -   Local tolerance of the subcutaneous treatment injection site(s)    -   Serum Pregnancy test (for nonsterile women of childbearing        potential)    -   Hematology    -   Clinical chemistry, coagulation, lipid, and urinalysis        (microscopic examination)    -   Blood sample collection for PK and PD analysis    -   Blood sample collection for exploratory biomarkers and retains    -   Tumor burden assessment using RECIST 1.1 will be done    -   Record any available clinically accepted assay results for        protein biomarkers relevant to the patient's specific tumor type        (e.g., PSA, CA-125, AFP, CEA, beta-hCG, CA19-9, etc.)    -   Review of adverse events

Study Endpoints

Safety Endpoints

-   -   Incidence, grade and duration of AEs    -   Global and local tolerability assessments    -   Laboratory assessments    -   Physical examinations, vital signs and ECG parameters

Pharmacokinetic and Tumor Burden Endpoints

-   -   PK profile from dose 1 until patient is no longer taking drug    -   Change in disease status, Overall response rate (CR+PR) and        disease control rate (CR+PR+SD)

Exploratory Endpoints

-   -   PET and DCE MRI assessments    -   PD (MetAP2) profile from dose 1 until the patient is no longer        taking study drug    -   MRI or CT assessments of change in body composition    -   Biomarker assessments (TNF-α, IL-6, MCP-1, IGF-1, hsCRP, leptin,        insulin, SHBG (for selected patients), VEGF, bFGF, and        adiponectin) from dose 1 until patient is no longer taking study        drug    -   Metabolic assessments (glucose, total cholesterol, LDL, HDL,        free fatty acids, lipids, triglycerides, and VLDL) and eating        and dietary assessments from dose 1 until patient is no longer        taking study drug

Statistical Analysis

Given the small patient sampling size in this Phase 1 trial, descriptivestatistics will be utilized for all safety, efficacy, andpharmacokinetic parameters. Categorical variables will be summarized byfrequency distributions (number and percentages of patients), continuousvariables will be summarized by mean, standard deviation, median,minimum, maximum, and time-to-event variables will be summarized usingKaplan-Meier methods and figures for the estimated median time.

Frequencies of patients experiencing at least one AE will be displayedby body system and preferred term according to MedDRA terminology.Detailed information collected for each AE will include: description ofthe event, duration, whether the AE was serious, severity, relationshipto study drug, action taken, clinical outcome, and whether or not it wasa DLT. Severity of the AEs will be graded according to the CTCAE v4.02.AEs classified as dose limiting will be listed.

Summary tables will present the number of patients (per dose group)observed with AEs and corresponding percentages. The denominator used tocalculate incidence percentages consists of patients receiving at leastone dose of COMPOUND 1 for each dose group. Within each table, the AEswill be categorized by MedDRA body system and preferred term. Additionalsubcategories will be based on event severity and relationship to studydrug.

Adverse events resulting in discontinuation of treatment or withdrawalfrom the study, serious adverse events, and deaths on-study will betabulated. All DLTs will be reported and the MTD identified.

Vital signs and ECGs will be summarized using descriptive statistics.Summary tables will be prepared to examine the distribution oflaboratory measures over time. Shift tables may be provided to examinethe distribution of laboratory toxicities. In addition, patient listingswill be presented for adverse events, vital signs, clinical laboratorytests, physical examinations, and ECGs (pre- and post-treatment).

Example 5 Phase 1 Studies—Metabolic Dysfunction

Metabolic dysfunction, defined as elevated levels of hormones such asinsulin, leptin, IGF-1 or low level of a hormone such as adiponectin oran elevated leptin:adiponectin ratio, is typically associated withobesity (defined as having a body mass index>30 kg/m2). Obesity mostoften results from over-nutrition and sedentary lifestyle, which overtime leads to increased nutrient storage as triglyceride within adiposetissue. In this scenario adipocytes within adipose tissue undergohypertrophy as more triglyceride is deposited and obesity develops, butthese cells eventually reach a critical size beyond which they cannotexpand. Hypertrophic adipocytes exhibit enhanced leptin secretion (whichleads to increased levels of circulating leptin, in proportion toadipose tissue mass) and reduced secretion of adiponectin (which leadsto lower levels of circulating adiponectin, indicative of metabolicdysfunction).

Additionally hypertrophic adipocytes create local hypoxia, which causescellular stress, cell death and concomitant infiltration of immune cells(macrophages and lymphocytes) to ingest excess triglyceride and cellulardebris. Subsequent events include sustained inflammation within adiposetissue, proliferation of adipose stem cells contributing to adipocytehyperplasia, increased angiogenesis all of which contribute todevelopment of metabolic dysfunction.

These events occurs principally in visceral (abdominal) adipose tissueas opposed to sub-cutaneous adipose tissue, and the association ofvisceral adipose tissue mass (but to a lesser degree, subcutaneousadipose tissue) with metabolic dysfunction is well known. However,because measurement of BMI does not capture adipose tissue distributionwithin the body or take into account muscle mass, hyper-adiposity andpathological disturbances in adipose tissue that lead to metabolicdysfunction as defined above, can all occur in patients with BMI in thenormal (e.g., 20-25 kg/m2) or overweight (e.g., 25-30 kg/m2) categories.In order to determine whether or not a patient has metabolicdysfunction, BMI is not accurate for the reasons stated above, and moreaccurate tests would involve measuring the levels of circulatinghormones such as insulin, leptin, adiponectin and IGF-1.

In the instant study, circulating hormones such as insulin, leptin,adiponectin and IGF-1 were measured in cancer patients (in the fastedstate), and the response to once-weekly subcutaneous dosing of Compound1, using a range of doses. It is noted that patients with carcinoid,colorectal, cervical, endometrial and breast cancer exhibited baselinelevels of such hormones indicating varying degrees of metabolicdysfunction. Furthermore, the directionality of changes in the level ofthese hormones following weekly administration of Compound 1 indicatesimprovement of metabolic dysfunction.

FIG. 12 shows circulating levels of metabolic biomarkers insulin,adiponectin, leptin, IGF-1 and the leptin:adiponectin ration (LAR) bothat baseline and after once weekly dosing of Compound 1 to a male patientwith carcinoid tumors and a BMI of 24.5 kg/m2 (e.g., normal). FIG. 12Ashows absolute values of the metabolic biomarkers and FIG. 12B shows %change relative to baseline over time. The results in FIGS. 12A and 12Bdemonstrate that the level of fasting insulin at baseline was abnormallyhigh but declined by 89% (relative to baseline) after four weekly dosesof Compound 1. In addition leptin levels as well as theleptin:adiponectin ratio (LAR) all decreased, indicating improvement inmetabolic function following administration of Compound 1.

In another example shown in FIG. 13, a female patient with colon cancer(BMI=23.5, or normal) was administered Compound 1 once-weekly at 6 mg/m²for 12 weeks followed by dose escalation (DE) to 8.5 mg/m² for anadditional six weeks. FIG. 13A shows absolute values of the metabolicbiomarkers and FIG. 18B shows % change over time. The results in FIGS.13A and 13B demonstrate that leptin declined from baseline whileadiponectin increased over the same time such that the LAR declined by62% from an elevated value of 4.7 at baseline, indicating improvementsin metabolic dysfunction following administration of Compound 1.

In another example shown in FIG. 14, a female patient with endometrialcancer (BMI=25.1, or overweight) was administered Compound 1 once-weeklyat 8.5 mg/m² for 12 weeks followed by dose-escalation (DE) to 11.9 mg/m²for an additional five weeks. FIG. 14A shows absolute values of themetabolic biomarkers and FIG. 14B shows % change over time. The resultsin FIGS. 14A and 14B demonstrate that leptin declined from baselinewhile adiponectin increased over the same time such that the LARdeclined by 85% from an elevated value of 4.5 at baseline, indicatingimprovements in metabolic dysfunction following administration ofCompound 1. Insulin data was not available at baseline, so %change frombaseline was not calculated, but insulin did decrease by 80% from theperiod beginning 4 weeks after initiating dosing (when data for insulinfirst became available) to 8 weeks after initiating dosing.

In another example shown in FIG. 15, a female patient with cervicalcancer (BMI=22.5, or normal) was administered Compound 1 once-weekly at11.9 mg/m² for 8 weeks. FIG. 15A shows absolute values of the metabolicbiomarkers and FIG. 15B shows % change over time. The results in FIGS.15A and 15B demonstrate that leptin declined by 88% from baseline andthe LAR declined by 78% from baseline, indicating improvements inmetabolic dysfunction after 8 weeks of dosing with Compound 1. Insulindecreased by 50% from baseline to 8 weeks post-dosing, also indicatingimprovements in metabolic dysfunction following administration ofCompound 1.

In another example shown in FIG. 16, a female patient with hormonereceptor-positive breast cancer (BMI=27.5, or overweight) wasadministered Compound 1 once-weekly at 15.3 mg/m² for 8 weeks. FIG. 16Ashows absolute values of the metabolic biomarkers and FIG. 16B shows %change over time. The results in FIGS. 16A and 16B demonstrate thatleptin declined by 70% from baseline indicating an improvement inmetabolic dysfunction after 8 weeks of dosing with Compound 1.

1. A method for treating, or ameliorating at least one symptom of,cancer in a subject in need thereof comprising administering attherapeutically effective amount of at least one compound of the Formula

wherein, independently for each occurrence, R₄ is H or C₁-C₆ alkyl; R₅is H or C₁-C₆ alkyl; R₆ is C₂-C₆ hydroxyalkyl; Z is—NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-L or—NH-AA₁-AA₂-AA₃-AA₄-AA₅-AA₆-C(O)-Q-X—Y—C(O)—W; AA₁ is glycine, alanine,or H₂N(CH₂)_(m)CO₂H, wherein m is 2, 3, 4 or 5; AA₂ is a bond, oralanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine,histidine, isoleucine, lysine, leucine, methionine, asparagine, proline,glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;AA₃ is a bond, or alanine, cysteine, aspartic acid, glutamic acid,phenylalanine, glycine, histidine, isoleucine, lysine, leucine,methionine, asparagine, proline, glutamine, arginine, serine, threonine,valine, tryptophan, or tyrosine; AA₄ is a bond, or alanine, cysteine,aspartic acid, glutamic acid, phenylalanine, glycine, histidine,isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine,arginine, serine, threonine, valine, tryptophan, or tyrosine; AA₅ is abond, or glycine, valine, tyrosine, tryptophan, phenylalanine,methionine, leucine, isoleucine, or asparagine; AA₆ is a bond, oralanine, asparagine, citrulline, glutamine, glycine, leucine,methionine, phenylalanine, serine, threonine, tryptophan, tyrosine,valine, or H₂N(CH₂)_(m)CO₂H, wherein m is 2, 3, 4 or 5; L is —OH,—O-succinimide, —O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, —NH₂, —NH(C₂-C₆ hydroxyalkyl),halide or perfluoroalkyloxy; Q is NR, O, or S; X isM-(C(R)₂)_(p)-M-J-M-(C(R)₂)_(p)-M-V; M is a bond, or C(O); J is a bond,or ((CH₂)_(q)Q)_(r), C₅-C₈ cycloalkyl, aryl, heteroaryl, NR, O, or S; Yis NR, O, or S; R is H or alkyl; V is a bond or

R⁹ is alkyl, aryl, aralkyl, or a bond; or R⁹ taken together with Y formsa heterocyclic ring; R¹⁰ is amido or a bond; R¹¹ is H or alkyl; W is aMetAP2 inhibitor moiety or alkyl; x is in the range of 1 to about 450; yis in the range of 1 to about 30; n is in the range of 1 to about 100; pis 0 to 20; q is 2 or 3; r is 1, 2, 3, 4, 5, or 6; or a pharmaceuticallyacceptable salt, prodrug, metabolite, analog or derivative thereof,wherein the subject has a metabolic dysfunction, and wherein the canceris treated.
 2. The method of claim 1, wherein the at least one compound,or a pharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, is selected from the group consisting of


3. The method of claim 1, wherein the at least one compound, or apharmaceutically acceptable salt, prodrug, metabolite, analog orderivative thereof, has the Formula


4. The method of claim 1, wherein R₄ is methyl.
 5. The method of claim1, wherein R₅ is methyl.
 6. The method of claim 1, wherein R₆ is2-hydroxypropyl.
 7. The method of claim 1, wherein Z is—NH-AA₆-C(O)-Q-X—Y—C(O)—W.
 8. The method of claim 7, wherein AA₆ isglycine.
 9. The method of claim 1, wherein Z is—NH-AA₅-AA₆-C(O)-Q-X—Y—C(O)—W.
 10. The method of claim 9, wherein AA₅ isleucine and AA₆ is glycine.
 11. The method of claim 9, wherein AA₅ isvaline and AA₆ is glycine.
 12. The method of claim 9, wherein AA₅ isphenylalanine and AA₆ is glycine.
 13. The method of claim 9, wherein AA₅is glycine and AA₆ is glycine.
 14. The method of claim 1, wherein Z is—NH-AA₃-AA₄-AA₅-AA₆-C(O)-Q-X—Y—C(O)—W.
 15. The method of claim 14,wherein AA₅ is leucine and each of AA₃, AA₄, or AA₆ is glycine.
 16. Themethod of claim 14, wherein AA₅ is valine and each of AA₃, AA₄, or AA₆is glycine.
 17. The method of claim 14, wherein AA₅ is phenylalanine andeach of AA₃, AA₄, or AA₆ is glycine.
 18. The method of claim 14, whereinAA₃ is glycine, AA₄ is phenylalanine, AA₅ is leucine and AA₆ is glycine.19. The method of claim 14, wherein each of AA₃, AA₄, AA₅ and AA₆ isglycine.
 20. The method of claim 1, wherein -Q-X—Y is


21. The method of claim 1, wherein W is


22. The method of claim 1, wherein the ratio of x toy is in the range ofabout 30:1 to about 3:1.
 23. The method of claim 1, wherein the ratio ofx to y is about 11:1.
 24. A method for treating, or ameliorating atleast one symptom of, cancer in a subject in need thereof comprisingadministering a therapeutically effective amount of at least onecompound, or a pharmaceutically acceptable salt, prodrug, metabolite,analog or derivative thereof, represented by: Z-Q-X—Y—C(O)—W wherein,independently for each occurrence, Z is —H, —H₂N-AA₃-AA₄-AA₅-AA₆-C(O)—or Z is H₂N-AA₅-AA₆-C(O); AA₃ is a bond, or alanine, cysteine, asparticacid, glutamic acid, phenylalanine, glycine, histidine, isoleucine,lysine, leucine, methionine, asparagine, proline, glutamine, arginine,serine, threonine, valine, tryptophan, or tyrosine; AA₄ is a bond, oralanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine,histidine, isoleucine, lysine, leucine, methionine, asparagine, proline,glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;AA₅ is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine,methionine, leucine, isoleucine, or asparagine; AA₆ is alanine,asparagine, citrulline, glutamine, glycine, leucine, methionine,phenylalanine, serine, threonine, tryptophan, tyrosine, valine orH₂N(CH₂)mCO₂H, wherein m is 2, 3, 4 or 5; Q is NR, O, or S; X isM-(C(R)₂)_(p)-M-J-M-(C(R)₂)_(p)-M-V; M is a bond, or C(O); J is a bond,or ((CH₂)_(q)Q)_(r), C₅-C₈ cycloalkyl, aryl, heteroaryl, NR, O, or S; Yis NR, O, or S; R is H or alkyl; V is a bond or

R⁹ is alkyl, aryl, aralkyl, or a bond; or R⁹ taken together with Y formsa heterocyclic ring; R¹⁰ is amido or a bond; R¹¹ is H or alkyl; W is aMetAP2 inhibitor moiety; p is 0 to 20; q is 2 or 3; and r is 1, 2, 3, 4,5, or
 6. wherein the subject has a metabolic dysfunction, and whereinthe cancer is treated. 25-36. (canceled)
 37. The method of claim 1,wherein the cancer is post-menopausal HR+/Her2− breast cancer,castration resistant prostate cancer, esophageal carcinoma, colorectaladenocarcinoma, cervical cancer, endometrial cancer, ovarian cancer,pancreatic adenocarcinoma, gall bladder cancer, liver cancer, clear-cellrenal cancer, melanoma, multiple myeloma, or combinations thereof. 38.The method of claim 1, wherein the metabolic dysfunction is excessivevisceral adiposity, elevated leptin levels, depressed adiponectinlevels, high leptin-to-adiponectin ratio, elevated fasting insulinlevels accompanied by chronic inflammation, or combinations thereof. 39.The method of claim 1, further comprising treating, or ameliorating atleast one symptom of, the metabolic dysfunction in said subject.
 40. Themethod of claim 1, further comprising increasing adiponectin, decreasingleptin, decreasing fasting insulin, or combinations thereof in saidsubject.
 41. The method of claim 1, wherein said therapeuticallyeffective amount is from about 0.0001 mg/kg to about 5 mg/kg of bodyweight per day.
 42. The method of claim 1, wherein said therapeuticallyeffective amount is from or about 0.001 to about 0.005 mg/kg of bodyweight per day.
 43. The method of claim 1, wherein said compound isadministered from about 1 to about 5 times per week.
 44. The method ofclaim 1, wherein said compound is administered in a q4d dosing schedule.45. The method of claim 1, wherein said compound is administered in aq7d dosing schedule.
 46. The method of claim 1, wherein said subject istreated for at least about six months.
 47. The method of claim 1,wherein said subject is treated for at least about one year.
 48. Themethod of claim 1, wherein said compound is administered parenterally.49. The method of claim 1, wherein said compound is administeredsubcutaneously.
 50. The method of claim 1, further comprisingadministering a second active agent.
 51. The method of claim 1, whereinsaid compound is provided as a pharmaceutical composition comprisingsaid compound and a pharmaceutically acceptable carrier.